CA2005337A1

CA2005337A1 - Use of peptide isosteres as retroviral protease inhibitors

Info

Publication number: CA2005337A1
Application number: CA002005337A
Authority: CA
Inventors: Alexander Fassler; Ernst Hungerbuhler; Johannes Rosel; Heinrich Rueger; Peter Schneider; Jeanette Wood
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1988-12-15
Filing date: 1989-12-13
Publication date: 1990-06-15
Also published as: AU4678589A; DK633189D0; JPH02212434A; EP0374097A3; IL92671A0; ZA899559B; DK633189A; EP0374097A2

Abstract

Use of peptide isosteres as retroviral protease inhibitors Abstract The invention relates to the use of compounds of the renin inhibitor type or related aspartate proteinase inhibitors as gag protease inhibitors. It relates especially to the use of those compounds for the manufacture of pharmaceutical preparations for use as gag protease inhibitors, there being used compounds of the formula wherein AAN is a bivalent radical, consisting of from one to five bivalent .alpha.-amino acid residues, which is bonded N-terminally to the radical R2 and C-terminally to the radical Q, AAC is a bond or a bivalent radical, consisting of from one to five bivalent .alpha.-amino acid residues, which is bonded N-terminally to the radical Q and C-terminally to the radical R1, R1 is hydroxy, etherified hydroxy, amino or substituted amino with the exception of an amino radical derived from an .alpha.-amino acid, R2 is hydrogen or an acyl radical with the exception of an unsubstituted or N-substituted acyl radical of a natural amino acid, and Q is a bivalent radical that is an isostere of a dipeptide, and salts thereof.

Description

3 5 ;~ 3 ~ !
, 4-17358/+

Use of peptide isosteres as retroviral protease inhibitors HIV (human immunodeficiency virus) is a retrovirus that causes the AIDSdisease which generally proves fatal in man. While it is today possible to alleviate the effects of AIDS and prolong patients' lives, there have hitherto been no pharmaceutical preparations that effectively combat the cause of AIDS. One possible aim in the treatment of AIDS is to prevent the propagation of HIV without at the same time damaging the still intact cell aggregates of the patient.

The genome of the two types of HIV, HIV-l and HIV-2, that are known so far has a region that codes for a "gag protease". In addition, both viruses contain a region that codes for the "group specific antigens"
(gag). The corresponding genes are expressed as prccursor proteln and the actual gag proteins are freed proteolytically therefrom by the above-mentioned gag protease. Gag protease itself is also excised from a pre-cursor protein from which further viral proteins, such as reverse tran-scriptase and integrase, originate. This process is presumed to proceed autoproteolytically. It is also known that gag protease cleaves the major core protein (p24) of HIV-1 and HIV-2 preferentially N-terminally at proline, for example at Phe-Pro, Leu-Pro or Tyr-Pro. A Pro-terminal p24 thus shortened is then used together with other viral structural proteins for the synthesis of the nucleocapsid and the virus coat of HIV-1 and HIV-2. It is also known that the HIV-1 gag protease cleaves Leu-Phe, Leu-Ala, Met-Met and Phe-Leu sequences with varying degrees of effi-ciency. It is clear that, in addition to the amino acid sequence, the conformation contributes to the specificity of gag protease.

~5;33~

If the action of gag protsase could be inhibited, neither functional structural proteins nor the necessary viral enzymes would be available to the virus and its propagation would be hindered, if not interrupted altogether. There is therefore a need for complete or at least partial inhibitors of gag protease. Such compounds would play an important role as antiviral agents against AIDS or other cetroviral diseases.

It is known that the gag protease of HIV can be classified as an aspartate proteinase and is inhibited by pepstatin. It has surprisingly been found that compounds of the renin inhibitor type or related ~-aspartate proteinase inhibitors are suitable as gag protease inhibitors since they are capable of inhibiting gag proteases even in the nanomolar concentration range. `` ~

The invention therefore relates to the use of compounds of the renin ~;
inhibitor type or related aspartate proteinase inhibitors as gag protease inhibitors. It relates especially to the use of compounds of that type that exhibit inhibitory effects of 50 % or more (ICso) when used at con-centrations of 10 6 mol/l or less against gag protease in the form of an isolated enzyme or when used at concentrations of 10 5 mol/l or less against gag protease in the cell.

Numerous compounds of the renin inhibitor type are already known. For example, European Patent Applications 143 746, 144 290, 184 550, 236 734, ~ `
118 223, 212 903, 45 665, 152 255, 156 322, 173 481, 163 237, 273 696, 161 588, 172 347, 77 028, 104 041, 155 809, 192 554, 209 848, 210 5~5, 211 580 and 237 202 disclose renin inhibitors the use of which as gag ~-protease inhibitors is included in this invention. `~ ~
: .
Related aspartate proteinase inhibitors are, for example, inhibitors of pepsin, chymosin, cathepsin D or penicillopepsin. -The invention relates especially to the use according to the invention of compounds of the formula I -R2 - AAN - Q - AAC - R1 ;

`.;,`".'''`' '" ';: '"~,.,-''''' '', '`".."' ,; `.,';' '' 2~ 3~

wherein M N is a bivalent radical, consisting of from one to five bivalent ~-amino acid residues, which is bonded N-terminally to the radical R2 and C-terminally to the radical Q, AAC is a bond or a bivalent radical, consisting of from one to five bivalent ~-amino acid residues, which is bonded N-terminally to the radical Q and C-terminally to the radical Rl, Rl is hydroxy, etherified hydroxy, amino or substituted amino with the exception of an amino radical derived from an ~-amino acid, R2 -is hydrogen or an acyl radical with the exception of an unsubstituted or N-substituted acyl radical of a natural amino acid, and Q is a bivalent radical that is an isostere of a dipeptide, and also to the use of salts of such compounds.

The abbreviation AAN denotes the amino acid sequence that is N-terminalto the dipeptide isostere Q (amino acid(s) N-terminal). The abbreviation AAC denotes the amino acid sequence that is C-terminal to the dipeptide isostere Q (amino acid(s) C-terminal). The C-terminal amino acid sequence may also be completely missing, in which case M C is a bond.

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

The substituted -carbon atoms of the amino acid residues of which AAN
and AAC consist may have the R-, S- or R,S-configuration. Compounds of the formula I in which these carbon atoms have the S-configuration are preferred. The ~-amino acid residues of the radical AAN may be substi-tuted N-terminally by lower alkyl, for example methyl or ethyl, in order to increase the stability of the compound of the formula I against enzymatic degradation.

A bivalent -amino acid residue of which AAN and AAC consist is, for example, a residue of a natural ~-amino acid having the L-configuration, as is normal in proteins, of a homologue of such an amino acid, for ~G)5~3~ ~

example in which the amino acid side chain is lengthened or shortened by one or two me~hylene groups and/or a methyl group has been replaced by hydrogen, of a substituted aromatic ~-amino acid, for example a substi-tuted phenylalanine or phenylglycine, in which the substituent(s) may be lower alkyl, for example methyl, halogen, for example fluorine, chlorine, bromine or iodine, hydroxy, lower alkoxy, for example methoxy, lower alkanoyloxy, for example acetoxy, amino, lower alkylamino, for example ;-methylamino, di-lower alkylamino, for example dimethylamino, lower alkanoylamino, for example acetylamino or pivaloylamino, lower alkoxy-carbonylamino, for example tert.-butoxycarbonylamino, arylmethoxycar-bonylamino, for example benzyloxycarbonylamino, and/or nitro and occur(s) one or more times, of a benzo-fused phenylalanine or phenylglycine, such as K-naphthylalanine, or of a hydrogenated phenylalanine or phenyl-glycinej such as cyclohexylalanine or cyclohexylglycine, of a five- or six-membered cyclic, benzo-fused ~-amino acid, for example indoline-2-carboxylic acid or 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, of a natural or homologous ~-amino acid in which a carboxy group of the side chain is in esterified or amidated form, for example in the form of a u lower alkyl ester group, such as methoxycarbonyl or tert.-butoxycarbonyl, or in the form of a carbamoyl group, a lower alkylcarbamoyl group, such ;`
as methylcarbamoyl, or a di-lower alkylcarbamoyl group, such as dimethyl-carbamoyl, in which an amino group of the side chain is in acylated form, for example in the form of a lower alkanoylamino group, such as acetyl-amino or pivaloylamino, in the form of a lower alkoxycarbonylamino group, such as tert.-butoxycarbonylamino, or in the form of an arylmethoxycar-bonylamino group, such as benzyloxycarbonylamino, or in which a hydroxy group of the side chain is in etherified or esterified form, for example in the form of a lower alkoxy group, such as methoxy, in the form of an aryl-lower alkoxy group, such as benzyloxy, or in the form of a lower ` `---alkanoyloxy group, such as acetoxy, or is a residue of an epimer of such an amino acid, that is to say having the non-naturally occurring D-con-figuration.
.',',:,, ~;
Such amino acids are, for example, glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (-aminovaleric acid), leucine (H-Leu-OH), isoleucine (H-Ile-OH), norleucine (~-aminohexanoic acid, 20(~337 H-Nle-OH), serine (H-Ser-OH), homoserine ~-amino-r-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-O~I), proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), tyrosine (H-Tyr-OH), ~-nitrophenylalanine, 4-aminophenyl-alanine, 4-chlorophenylalanine, ~-phenylserine (~-hydroxyphenylalanine), phenylglycine, ~-naphthylalanine (I~-Nal-OH), cyclohexylalanins (H-~ha-OH), cyclohexylglycine, tryptophan ~H-Trp-OH), indoline-2-car-boxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asn-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH), glutamic acid mono-tert.-butyl ester, glutamine (H-Gln-OH), N -dimethylglutamine, histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), N -tert.-butoxycarbonyl-lysine, ~-hydroxylysine, ornithine (~,~-diaminovaleric acid), N~-pivaloyl-ornithine, ,r-diaminobutyric acid or ,~-diaminopropionic acid.

The general terms and expressions used in the description of the present invention have preferably the following meanings:

An etherified hydroxy group Rl is preferably etherified by organic radicals that can be removed under physiological conditions and that, after removal, produce cleavage products that are pharmacologically harmless in the concentration concerned.

Etherified hydroxy Rl is, for example, acyloxy-lower alkoxy in which acyl is the acyl group of an optionally branched lower alkanecarboxylic acid or of carbonic acid mono-esterified by optionally branched lower alkyl, for example lower alkanoyloxy-lower alkoxy, such as acetoxymethoxy, l-acetoxyethoxy, pivaloyloxymethoxy or l-pivaloyloxyethoxy, or lower alkoxycarbonyloxy-lower alkoxy, such as ethoxycarbonyloxymethoxy, l-ethoxycarbonyloxyethoxy, tert.-butoxycarbonyloxymethoxy or l-~ert.-butoxycarbonyloxyethoxy.

Etherified hydroxy Rl is also preferably lower alkoxy, for example methoxy or ethoxy, aryloxy, for example phenoxy, or aryl-lower alkoxy, for example benzyloxy.

5~3~

Substituted amino Rl is, for example, an amino group that is substituted by one or optionally two organic radicals, for example unsubstituted or substituted, saturated or unsaturated, alipha~ic hydrocarbon radicals having up to and including 18, preferably up to and including 10, carbon atoms or unsubstituted or substituted, aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic radicals having up to 18, preferably up to and including 10, carbon atoms.

Excluded as substituted amino R1 is the radical of an ~-amino acid or its N-substituted, esterified or amidated derivatives. ;

An unsubstituted or substituted, saturated or unsaturated, aliphatic hydrocarbon radical that substitutes the amino group Rl is, for example, unsubstituted or substituted alkyl having up to 10 carbon atoms, lower alkenyl or lower alkynyl having up to and including 7 carbon atoms, or cycloalkyl or cycloalkyl-lower alkyl having from 4 to 10 carbon atoms.
These radicals can be substitutod by one or more of the functional groups mentioned in connection with lower alkyl Ra defined hereinafter, and by sulfo.

Preforred substituents are hydroxy, lower alkoxy, for example methoxy, lower alkanoyloxy, for example acetoxy, substituted or unsubstituted phenoxy, for example carbamoylphenoxy or carbamoyl-hydroxy-phenoxy, car-boxy, esterified carboxy, for example lower alkoxycarbonyl, such as methoxycarbonyl or tert.-butoxycarbonyl, or a physiologically cleavable esterified carboxy, for example l-(lower alkanoyloxy)-lower alkoxycar-bonyl, such as acetoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl or ;;
l-propionyloxyethoxycarbonyl, l-(lower alkoxycarbonyloxy)-lower alkoxy- ,;~
carbonyl, such as l-(ethoxycarbonyloxy)-ethoxycarbonyl, or ~-amino-lower alkanoyloxymethoxycarbonyl, such as ~-aminoacetoxymethoxycarbonyl or (S)-~-amino-~-methylbutyryloxymethoxycarbonyl, carbamoyl, substituted or ~ ~
unsubstituted lower alkylcarbamoyl, for example hydroxy-lower alkylcar- -bamoyl, such as 2-hydroxyethylcarbamoyl or tris-(hydroxymethyl)-methyl- , carbamoyl, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, lower alkoxycarbonylamino, for example tert.-butoxycarbonylamino, guanidino, saturated five- or six-" :' '"' ,.'" ~'~,'~

:: .: : - . - . . . , ;. :., . - - .. . : . - . ... , . .. - ..... .. . .. .

j ~
` 2Cl1(3~33~
!

membered heterocyclyl that is bonded v1a a nitrogen atom and, if desired, substituted by oxo, for example 1-piperidinyl, 4-morpholinyl or 2-oxo-1-pyrrolidinyl, or sulfo.

An aromatic or aromatic-aliphatic radical in a group Rl preferably has the same meanings as those mentioned hereinafter under aryl Ra or Rb or aryl-lower alkyl Ra and is, for example, phenyl or phenyl-lower alkyl.

These radicals may be substituted in the aromatic moiety, for example by lower alkyl, for example methyl or ethyl, hydroxy, etherified hydroxy, for example lower alkoxy, such as methoxy or tert.-butoxy, esterified hydroxy, for example lower alkanoyloxy, such as acetoxy, or halogen, for example fluorine or chlorine, carboxy, esterified carboxy, for example lower alkoxycarbonyl, such as tert.-butoxycarbonyl, carbamoyl, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, acylated amino, for example lower alkoxycarbonyl-amino, such as tert.-butoxycarbonylamino, and also by nitro.

Lower alkyl in a phenyl-lower alkyl radical may be substituted by the same substituents as may alkyl in a radical Rl. . .

A heteroaromatic or heteroaromatic-aliphatic radical in a group Rl pre-ferably has the same meanings as those mentioned hereinafter under heteroaryl R and R or heteroaryl-lower alkyl R and is, for example, pyridyl-lower alkyl, for example 2-, 3- or 4-pyridylmethyl, imidazolyl-lower alkyl, for example 2-(4-imidazolyl)-ethyl or also 2-(2-[4-imidazolyl]-ethylamino)-ethyl, or indolyl-lower alkyl, for example 3-indolylmethyl or 2-(3 indolyl)-ethyl.

Substituted amino Rl is preferably alkylamino, for example methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl-, isobutyl-, tert.-butyl-, n-pentyl-, isopentyl-5 n-hexyl-, n-octyl- or n-decyl-amino, di-lower alkylamino, for example dimethylamino or diethylamino, hydroxy-lower alkylamino, for example 2-hydroxyethylamino, 1-hydroxybut-2-ylamino, 5-hydroxypentylamino or tris(hydroxymethyl)-methylamino, di-(hydroxy-lower alkyl)-amino, for example di-(2-hydroxyethyl)-amino, lower alkoxy-lower alkylamino, for example 2-methoxyethylamino, lower alkanoyloxy- ~ -lower alkylamino, for example 2-acetoxyethylamino, phenoxy-lower alkyl-amino or phenoxy-hydroxy-lower alkylamino in which phenoxy is unsubsti- ::tuted or substituted by lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or by carbamoyl, for example 2-phenoxyethylamino, 2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino or 3-(3-carbamoylphenoxy)-2-hydroxypropylamino, carboxyalkylamino or amino-carboxy-alkylamino in which the carboxy radical is not in the 1-position of the alkyl radical, for example 4-carboxy-n-butylamino, 5-carboxy-n-pentylamino, 5-amino-5- - ~:
carboxy-n-pentylamino, 6-carboxy-n-hexylamino, 7-carboxy-n-heptylamino or 8-carboxy-n-octylamino, also dicarboxymethylamino, lower alkoxycarbonyl-alkylamino or acylamino-lower alkoxycarbonylalkylamino in which the car-bonyl radical is not in the 1-position of the alkyl radical, for example 4-tert.-butoxycarbonyl-n-butylamino, 5-tert.-butoxycarbonylamino-5-methoxycarbonyl-n-pentylamino, 7-tert.-butoxycarbonyl-n-heptylamino or 8-tert.-butoxycarbonyl-n-octylamino, also di-lower alkoxycarbonyl-methyl- .~
amino, for example di-methoxycarbonyl-methylamino, physiologically ; .
cleavable esterified carboxyalkylamino in which the ester function is not in the l-position of the alkyl radical, for example 4-pivaloyloxymethoxy-carbonyl-n-butylamino, 7-(1-ethoxycarbonyloxyethoxycarbonyl)-n-heptyl- :~
amino or 7-pivaloyloxymethoxycarbonyl-n-heptylamino, carbamoylalkylamino or hydroxy-lower alkylcarbamoylalkylamino in which the carbamoyl radical ~
is not in the 1-position of the alkyl radical, for example 4-carbamoyl-n- .1.::
butylamino, 7-carbamoyl-n-heptylamino or 4-(tris[hydroxymethyl]-methyl)- .
carbamoyl-n-butylamino, also dicarbamoyl-methylamino, di-(lower alkylcar- :.
bamoyl)-methylamino, for example di-(methylcarbamoyl)-methylamino, di- ~ .(hydroxy-lower alkylcarbamoyl)-methylamino, for example di-(2-hydroxy-ethylcarbamoyl)-methylamino, or bis-(di-lower alkylcarbamoyl)-methyl- : :
amino, or example bis-(dimethylcarbamoyl)-methylamino, amino-lower alkylamino, for example 2-aminoethylamino or 4-aminobutylamino, lower ~ :
alkylamino-lower alkylamino, for example 2-methylaminoethylamino, di-lower alkylamino-lower alkylamino, for example 2-dimethylaminoethylamino or 3-dimethylaminopropylamino, lower alkoxycarbonylamino-lower alXyl- ~ :
amino, for example 2-(tert.-butoxycarbonylamino)-ethylamino, guanidino-lower alkylamino, for example 2-guanidinoethylamino, saturated five- or six-membered heterocyclyl-lower alkylamino that is bonded via a nitrogen , '' '::

-21;~Q533~
_ 9 _ atom, for example 2-(4-morpholinyl)-ethylamino, 3-(4-morpholinyl)-propyl-amino or 3-(2-oxo-1-pyrrolidinyl~-propylamino, lower alkenylamino, for example allylamino or 2- or 3-butenylamino, lower alkynylamino, for example propargylamino, cycloalkylamino, for example cyclohexylamino or decahydronaphthylamino, cycloalkyl-lower alkylamino, for example cyclo-propylmethylamino or cyclohexylmethylamino~ naphthylamino, phenylamino or phenyl-lower alkylamino in which phenyl or naphthyl is unsubstituted or mono- or poly-substituted by lower alkyl, for example methyl, phenyl, hydroxy, lower alkoxy, for example methoxy or tert.-butoxy, lower alkanoyloxy, for example acetoxy, halogen, for example fluorine or ~ -chlorine, carboxy, lower alkoxycarbonyl, for example tert.-butoxycar-bonyl, carbamoyl, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, acylamino, for example tert.-butoxycarbonylamino and/or by nitro, for example phenylamino, 2-, 3- or 4-methylphenylamino, 4-biphenylylamino, 4-hydroxyphenylamino, 4-methoxyphenylamino, 2,3-, 2,4- or 2,5-dimethoxyphenylamino, 4-chloro-phenylamino, 2-, 3- or 4-carboxyphenylamino, 2-, 3- or 4-methoxy- or tert.-butoxy-carbonylphenylamino, 2-, 3- or 4-carbamoylphenylamino, 4-aminophenylamino, 4-tert.-butoxycarbonylaminophenylamino or 4-nitro-phenylamino, also, for example, benzylamino, 4-methylbenzylamino, 4~biphenylylmethylamino, 4-methoxybenzylamino, 2-, 3- or 4-carboxybenzyl-amino, 2-, 3- or 4-tert.-butoxycarbonylbenzylamino, 2-, 3-or 4-carbamoyl-benzylamino, 2-phenylethylamino, 3-phenylpropylamino or 5-phenylpentyl-amino, pyridyl-lower alkylamino, for example 2-, 3- or 4-pyridylmethyl-amino, 2-(2-, 3- or 4-pyridyl)-ethylamino or 3-(2-, 3- or 4-pyridyl)-propylamino, imidazolyl-lower alkylamino, for example 4-imidazolylmethyl-amino, 2-(4-imidazolyl)-ethylamino or 2-(2-[4-imidazolyl]-ethylamino)-ethylamino, indolyl-lower alkylamino, for example 3-indolylmethylamino or 2-(3-indolyl)-ethylamino, or sulfo-lower alkylamino, for example 2-sulfo-ethylamino.

Acyl R2 has, for example, up to 25, preferably up to 19, carbon atoms and is especially the acyl group of a carboxylic acid, of a semiester of carbonic acid, of an unsubstituted or N-substituted carbamic or thio-... . .. . . . .

~5~33~

`
carbamic acid, of an unsubstituted or N-substituted oxalamide, of a phosphoric acid, of a sulfonic acid or of an unsubstituted or N-substi-tuted amidosulfonic acid.
.
Preferred acyl groups R2 are, for example, alkanoyl, for example n-decanoyl, or lower alkanoyl, for example formyl, acetyl, propionyl or pivaloyl, hydroxy-lower alkanoyl, for example ~-hydroxypropionyl, lower alkoxy-lower alkanoyl, for example lower alkoxyacetyl or lower alkoxy-propionyl, such as methoxyacetyl or ~-methoxypropionyl, phenoxy-lower : :alkanoyl, for example phenoxyacetyl, naphthoxy-lower alkanoyl, for example a or ~-naphthoxyacetyl, lower alkanoyloxy-lower alkanoyl, for :
example lower alkanoyloxyacetyl or lower alkanoyloxypropionyl, such as acetoxyacetyl or ~-acetoxypropionyl, halo-lower alkanoyl, for example `:
-haloacetyl, such as -chloro-, -bromo-, -iodo- or ,,-trichloro- :
acetyl, or halopropionyl, such as ~-chloro- or ~-bromo-propionyl, car- .~
boxy-lower alkanoyl, for example carboxyacetyl or ~-carboxypropionyl, .. ..
lower alkoxycarbonyl-lower alkanoyl, for example lower alkoxycarbonyl- ::
acetyl or lower alkoxycarbonylpropionyl, such as methoxycarbonylacetyl, :
~-methoxycarbonylpropionyl, ethoxycarbonylacetyl or ~-ethoxycarbonyl- ~ -:
propionyl, carbamoyl-lower alkanoyl, for example carbamoylacetyl or ! , .
~-carbamoylpropionyl, lower alkylcarbamoyl-lower alkanoyl, for example methylcarbamoylacetyl, di-lower alkylcarbamoyl-lower alkanoyl, for example dimethylcarbamoylacetyl, oxo-lower alkanoyl, for example aceto-acetyl or propionylacetyl, hydroxy-carboxy-lower alkanoyl, for example -hydroxy-~-carboxy-acetyl or ~-hydroxy-~ carboxy-propionyl, hydroxy-lower alkoxycarbonyl-lower alkanoyl, for example -hydroxy--ethoxy- or -methoxy-carbonyl-acetyl or -hydroxy-~-ethoxy-or -methoxy-carbonyl- :
propionyl, esterified hydroxy-lower alkoxycarbonyl-lower alkanoyl, for .
example -acetoxy--methoxycarbonyl-acetyl, dihydroxy-carboxy-lower :
alkanoyl, for example ~,~-dihydroxy-~-carboxy-propionyl, dihydroxy-lower .
alkoxycarbonyl-lower alkanoyl, for example ,~-dihydroxy-~-ethoxy- or:;:
-methoxy-carbonyl-propionyl, esterified dihydroxy-lower alkoxycarbonyl-lower alkanoyl, for example ~,~-diacetoxy-~-methoxycarbonyl-propionyl, -naphthoxy-carboxy-lower alkanoyl, for example 2--naphthoxy-4-carboxy-butyryl, -naphthoxy-lower alkoxycarbonyl-lower alkanoyl, for example -naphthoxy-ethoxycarbonyl-acetyl, 2--naphthoxy-3-ethoxycarbonyl-pro- : .
, : . :

~0~ 37 pionyl, or 2-~-naphthoxy-4-tert.-butoxycarbonyl-butyryl, ~-naphthoxy-benzyloxycarbonyl-lower alkanoyl, for example 2-~-naphthoxy-3-benzyloxy-carbonyl-propionyl, ~-naphthoxy-carbamoyl-lower alkanoyl, for example 2-~-naphthoxy-4-carbamoyl-butyryl, ~-naphthoxy-cyano-lower alkanoyl, Eor example -naphthoxy-cyano-acetyl or 2-~-naphthoxy-4-cyano-butyryl, ~-naphthoxy-di-lower alkylamino-lower alkanoyl, for example 2--naphthoxy-5-dimethylamino-pentanoyl, ~-naphthoxy-oxo-lower alkanoyl, for example 2-~-naphthoxy-4-oxo-pentanoyl, heterocyclyl-lower alkanoyl, for example indolylacetyl or benzofuranylacetyl, lower alkenoyl, for example acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl, lower alkynoyl, for example propioloyl or 2- or 3-butynoyl, cycloalkylcarbonyl, for example cyclopropyl-, cyclobutyl-, cyclopentyl-or cyclohexyl-carbonyl, bicycloalkylcarbonyl, for example decahydronaphthyl-2-carbonyl, endo- or exo-norbornyl-2-carbonyl, bicyclo[2.2.2]oct-2-ylcarbonyl or bicyclo-[3.3.1]non-9-ylcarbonyl, tricycloalkylcarbonyl, for example 1- or 2-adamantylcarbonyl, cycloalkenylcarbonyl, for example l-cyclohexenyl-carbonyl or 1,4-cyclohexadienylcarbonyl, bicycloalkenylcarbonyl, for example 5-norbornen-2-ylcarbonyl or bicyclo[2.2.2]octen-2-ylcarbonyl, cycloalkyl-lower alkanoyl, for example cyclopropylacetyl, cyclopentyl-acetyl, cyclohexylacetyl or 3-cyclohexylpropionyl, cycloalkyl-lower alkenoyl, for example cyclohexylacryloyl, cycloalkenyl-lower alkanoyl, for example l-cyclohexenylacetyl or 1,4-cyclohexadienylacetyl, benzoyl unsubstituted or mono- or poly-substituted by lower alkyl, for example methyl, phenyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example methoxy, and/or by nitro, for example 4-chloro-, 4-methoxy- or 4-nitro-benzoyl, also phenyl-, ~-naphthyl- or ~-naphthyl-lower alkanoyl in which phenyl may be unsubstituted or mono- or poly-substituted by lower alkyl, for example methyl, phenyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example methoxy, and/or by nitro and in which i-lower alkanoyl may be unsubstituted or substituted, for example, by hydroxy, lower a~koxy, acyloxy, carboxy, esterified carboxy, carbamoyl, substituted carbamoyl, cyano, phosphono, esterified phosphono, benzo-furanyl and/or by oxo and is optionally branched, for example phenyl-acetyl, ~-naphthylacetyl, ~-naphthylacetyl, lower alkylphenylacetyl, such as 4-methylphenylacetyl, lower alkoxyphenylacetyl, such as 4-methoxy-phenylacetyl, 3-phenylpropionyl, 3-(~-hydroxyphenyl)-propionyl, diphenyl-~'"''.'~';'',' ~, .;.' 2~ 3~
- 12 - - :

acetyl, di-(4-methoxyphenyl)-acetyl, triphenylacetyl, substituted :`
anilinophenylacetyl, such as 2-(o,o-dichloroanilino)-phenylacetyl or 2-(o,o-dichloro-N-benzylanilino)-phenylacetyl~ 3-~- or -~-naphthylpro-pionyl, 3-phenyl- or 3-~-naphthyl-2-hydroxy-propionyl, 3-phenyl- or 3--naphthyl-2-lower alkoxy-propionyl, such as 3-phenyl- or 3-~-naphthyl-2- .
neopentyloxy-propionyl, 3-phenyl- or 3-~-naphthyl-2-acyloxy-propionyl, :
such as 3-phenyl-2-pivaloyloxy- or -2-acetoxy-propionyl, 3--naphthyl-2- .
pivaloyloxy- or -2-acetoxy-propionyl, 3-~-naphthyl-2-acetoacetoxy-pro-pionyl, 3-~-naphthyl-2-ethylaminocarbonyloxy-propionyl or 3-~-naphthyl-2-(2-amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy)-propionyl, : .3-phenyl- or 3--naphthyl-2-carboxymethyl-propionyl, 3-phenyl- or 3-~
naphthyl-2-lower alkoxycarbonyl-propionyl, such as 3--naphthyl-2-ethoxy-carbonyl-propionyl, 3-phenyl- or 3--naphthyl~2-benzyloxycarbonylmethyl-propionyl, 3-phenyl- or 3--naphthyl-2-carbamoyl-propionyl, 3-phenyl- or 3--naphthyl-2-tert.-butylcarbamoyl-propionyl, 3-phenyl- or 3-~-naphthyl-2-(2-dimethylaminoethyl)-carbamoyl-propionyl, 3--naphthyl-2-(carboxy- or tert.-butoxycarbonyl)-methylcarbamoyl-propionyl, 3-phenyl- or 3--naphthyl-2-(3-hydroxy-2-propyl)-carbamoyl-propionyl, 3-phenyl- or 3--naphthyl-2-(2,2-dimethoxyethyl)-carbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2-(5-amino-5-carboxypentyl)-carbamoyl-propionyl, 3-phenyl-or :
3-~-naphthyl-2-cyano-propionyl, 3-phenyl- or 3--naphthyl-2-cyanomethyl- : .
propionyl, 3-phenyl-2-phosphono- or -phosphonomethyl-propionyl, 3-phenyl-2-dimethoxyphosphoryl- or -dimethoxyphosphorylmethyl-propionyl, 3-phenyl-2-diethoxyphosphoryl- or -diethoxyphosphorylmethyl-propionyl, 3-phenyl-2-ethoxy- or -methoxy-hydroxyphosphoryl-propionyl, 3-phenyl- or 3--naphthyl-2-acetonyl-propionyl, 3-phenyl- or 3--naphthyl-2-dimethylamino-methyl-propionyl9 2-benzyl- or 2--naphthylmethyl-4-cyano-butyryl, 4-phenyl- or 4--naphthyl-3-carboxy-butyryl, 4-phenyl- or 4--naph~hyl-3-benzyloxycarbonyl-butyryl, 2-benzyl-4-(2-benzofuranyl)-4-oxo-butyryl, 2-benzyl- or 2--naphthylmethyl-4-oxo-pentanoyl, 2-benzyl- or 2--naphthylmethyl-4,4-dimethyl-3-oxo-pentanoyl, 2-benzyl- or 2--naphthyl-methyl-5-dimethylamino-pentanoyl, 2-benzyl- or 2-~-naphthylmethyl-5-dimethylamino-4-oxo-pentanoyl, 2-benzyl- or 2--naphthylmethyl-5,5-dimethyl-4-oxo-hexanoyl, ,p-diamino-phenylacetyl, ,~-diacylamino-phenylacetyl, such as ,~-dibenzyloxycarbonylamino-phenylacetyl or -pivaloylamino-~-benzyloxycarbonylamino-phenylacetyl, phenyl-lower 33~ :

alkenoyl, for example ~-phenyiacryloyl or ~-phenylvinylacetyl, naphthyl-carbonyl, for example ~- or R-naphthylcarbonyl or 1,8-naphthalenedicar-bonyl, indenylcarbonyl, for example 1-, 2- or 3-indenylcarbonyl, indanyl-carbonyl, for example 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, for example 9-phenanthrenylcarbonyl, unsubstituted or substituted pyrrolyl-carbonyl, for example 2- or 3-pyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl, furylcarbonyl, for example 2-furylcarbonyl, thienylcarbonyl, for example 2-thienylcarbonyl, pyridylcarbonyl, for example 2-, 3- or 4-pyridylcarbonyl, unsubstituted or substituted indolylcarbonyl, for example 2-, 3- or 5-indolylcarbonyl, l-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-indolyl-2-carbonyl, l-benzyl-indolyl-2- or -3-carbonyl, 4,5,o,7-tetrahydroindolyl-2-carbonylj cyclo-hepta[b]pyrrolyl-5-carbonyl, unsubstituted or substituted quinolylcar-bonyl, for example 2-, 3- or 4-quinolylcarbonyl or 4-hydroxyquinolyl-2-carbonyl, unsubstituted or substituted isoquinolylcarbonyl, for example 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-dihydroisoquinolyl-3-car-bonyl, 2-quinoxalinylcarbonyl, 2-benzofuranylcarbonyl, 3-chromancarbonyl, 3-thiochromancarbonyl, benz[e]indolyl-2-carbonyl, ~-carbolinyl-3-car-bonyl, pyrrolidinyl-3-carbonyl, hydroxypyrrolidinylcarbonyl, for example 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrolidinylcarbonyl, for example 5-oxopyrrolidinyl-2-carbonyl, piperidinylcarbonyl, for example 2-, 3- or 4-piperidinylcarbonyl, indolinylcarbonyl, for example 2- or 3-indolinylcarbonyl, 1,2,3,4-tetrahydroquinolylcarbonyl, for example 1,2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3,4-tetrahydro-isoquinolylcarbonyl, for example 1,2,3,4-tetrahydroisoquinolyl-1-, -3- or -4-carbonyl or 1-oxo-1,2,3,4-tetrahydroisoquinolyl-3-carbonyl, lower alkoxycarbonyl, for example methoxy-, ethoxy- or tert.-lower alkoxy-car-bonyl, such as tert.-butoxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2-chloro-, 2-bromo-, 2-iodo- or 2,2,2-trichloro-ethoxycarbonyl, aryl-lower alkoxycarbonyl, for example arylmethoxycarbonyl, in which aryl is phenyl, biphenylyl~ 1- or 2-naphthyl, fluorenyl, or phenyl mono- or -~
poly-substituted by lower alkyl, for example methyl or tert.-butyl, lower alkoxy, for example methoxy, ethoxy or tert.-butoxy, hydroxy, halogen, -for example chlorine or bromine, and/or by nitro, for example phenyl- ~-~
lower alkoxycarbonyl, such as benzyloxycarbonyl, 4-methoxybenzyloxycar-bonyl, 4-nitrobenzyloxycarbonyl, diphenyl-lower alkoxycarbonyl, such as :';' ;' '''`:
''.:,'~, ~
' .'. ~ ~''".

Z~(~5~37 :

diphenylmethoxycarbonyl, di-(4-methoxyphenyl)-methoxycarbonyl or trityloxycarbonyl, fluorenyl-lower alkoxycarbonyl, such as 9-fluorenyl-methoxycarbonyl, and also oxamoyl or lower alkyloxamoyl, for example methyl- or ethyl-oxamoyl.

Acyl R2 is also especially an acyl group of a saturated or unsaturated,aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, aromatic-aliphatic, heteroaromatic or heteroaromatic-aliphatic carboxylic acid, with the exception of the unsubstituted or N-substituted natural amino acid methionine, which acyl group is substituted by a thio, sulfinyl or sulfonyl group and optionally by other groups containing hetero atoms.
~''.
Preferred substituents R2 are acyl groups of the formula R - ~ - (CHz) - CH - (CHz) - ~ - (Ia), m (CHz)q Rb ::.' wherein Ra is unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tri-cycloalkyl or cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl or aryl-lower ;
alkenyl, unsubstituted or substituted heteroaryl or heteroaryl-lower alkyl, unsubstituted or substituted hydroxy or unsubstituted or substi-tuted amino, R is hydrogen, mono-, bi- or tri-cycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl, _ is 0, 1 or 2, n is 0, 1 or 2, p is 0, 1 or 2 and q is 0, 1, 2, 3 or 4.
~ :' The methine carbon atom in the partial formula Ia and, if _ is 1, also the sulfur atom may be in the R-, S- or R,S-configuration.

Lower alkyl R preferably has from 1 to 7 carbon atoms and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert.-butyl, each of which may be substituted by one or more functional groups, for example hydroxy, etherified hydroxy, for example lower alkoxy, such as methoxy or ethoxy, or phenoxy, esterified hydroxy, for example lower alkanoyloxy, 2Q~5~37 such as acetoxy, halogen, for example chlorine or bromine, hydroxysul-fonyloxy, carboxy, esterified carboxy, for example lower alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl, amidated carboxy, for example car-bamoyl or mono- or di-lower alkylcarbamoyl, such as methyl- or dimethyl-carbamoyl, cyano, amino, substituted amino~ for example mono-lower alkyl-amino, di-lower alkylamino, acylamino, or substituted amino in which the amino group is part of a five-or six-membered heterocycle containing one or two nitrogen atoms and, if desired, an oxygen or sulfur atom, or by oxo.

Substituted lower alkyl Ra is, for example, hydroxy-lower alkyl, for example 2-hydroxyethyl, lower alkoxy-lower alkyl, for example lower alkoxyethyl, such as 2-methoxyethyl, phenoxy-lower alkyl, for example 2-phenoxyethyl, lower alkanoyloxy-lower alkyl, for example lower alkanoyloxyethyl, such as 2-acetoxyethyl, halo-lower alkyl, for example haloethyl, such as 2-chloro- or 2-bromo-ethyl, hydroxysulfonyloxy-lower alkyl, for example 2-hydroxysulfonyloxyethyl, carboxy-lower alkyl, for :.
example carboxymethyl or 2-carboxyethyl, lower alkoxycsrbonyl-lower alkyl, for example lower alkoxycarbonylmethyl or lGwer alkoxycarbonyl- .~:
ethyl, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycar- ::
bonylmethyl or 2-ethoxycarbonylethyl, carbamoyl-lower alkyl, for example ; ~:
carbamoylmethyl or 2-carbamoylethyl, lower alkylcarbamoyl-lower alkyl, `~
for example methylcarbamoylmethyl, di-lower alkylcarbamoyl-lower alkyl, ;~
for example dimethylcarbamoylmethyl, cyano-lower alkyl, for example :` :
2-cyanoethyl, amino-lower alkyl, for example 2-aminoethyl, lower alkyl-amino-lower alkyl, for example 2-methylaminoethyl, di-lower alkylamino- `~
lower alkyl, for example 2-dimethylaminoethyl, morpholino-lower alkyl, for example 2-morpholinoethyl, piperidino-lower alkyl, for example 2-piperidinoethyl, acylamino-lower alkyl, for example lower alkanoyl- -amino-lower alkyl, such as 2-acetylaminoethyl, benzyloxycarbonylamino-lower alkyl, such as 2-benzyloxycarbonylaminoethyl, lower alkoxycarbonyl-amino-lower alkyl, such as 2-tert.-butoxycarbonylaminoethyl, or oxo-lower alkyl, for example 2-oxopropyl or 2-oxobutyl. ~ ;~

: .. ~ . .: ::

, ,.~: , , : :~ :,~.. ,';
- . . ~

.
~ \
2~

Lower alkenyl Ra contains, for example, from 2 to 7, especially from 2 to 4, carbon atoms and is, for example, vinyl, allyl or 2- or 3-butenyl.
Lower alkenyl Ra may be substituted by the same substituents as may lower alkyl, for example by hydroxy, etherified hydroxy, for example methoxy, esterified hydroxy, for example acetoxy, halogen, for example chlorine or bromine, carboxy, esterified carboxy, for example methoxycarbonyl or ethoxycarbonyl, or by amidated carboxy, for example carbamoyl.

Lower alkynyl Ra contains, for example, from 2 to 7, especially from 2 to 4, carbon atoms and is, for example, ethynyl, l-propynyl or 2-propynyl.

Cycloalkyl Ra or Rb contains, for example, from 3 to 8, especially from 3 to 6, carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclo-pentyl or cyclohexyl.
' "' Bicycloalkyl Ra or Rb contains, for example, from 5 to 10, especially from 6 to 9, carbon atoms and is, for example, bicyclo-hexyl, -heptyl, ~octyl, -nonyl or -decyl, for example bicyclo[3.1.0]hex-1-, -2- or -3-yl, bicyclo[4.1.0]hopt-1- or -7-yl, bicyclo[2.2.1]hept-2-yl, for example endo- or exo-norbornyl, bicyclo[3.2.1]oct-2-yl, bicyclo[3.3.0]oct-3-yl or bicyclo[3.3.1]non-9-yl, also ~- or ~-decahydronaphthyl.

Tricycloalkyl R or Rb contains, for example, from 8 to 10 carbon atoms and is, for example, tricyclo[5.2.1.02'6]dec-8-yl or adamantyl, such as l-adamantyl. -Cycloalkyl-lower alkyl R contains, for example, from 4 to 10, especially from 4 to 7, carbon atoms and is, for example, cyclopropylmethyl, cyclo-butylmethyl, cyclopentylmethyl or cyclohexylmethyl.

The cycloaliphatic or cycloaliphatic-aliphatic radicals mentioned may be substituted by the same substituents as may lower alkyl Ra.

Aryl R or R contains, for example, from 6 to 14 carbon atoms and is, for example, phenyl, indenyl, for example 2- or 4-indenyl, 1- or 2-naphthyl, anthryl, for example 1- or 2-anthryl, phenanthryl, for 20~337 example 9-phenanthryl, or acenaphthenyl, for example l-acenaphthenyl.
Aryl R or R is substituted, for example, by lower alkyl, for example methyl, phenyl, hydroxy, lower alkoxy, for example methoxy, acyloxy, for example lower alkanoyloxy, such as acetoxy, amino, lower alkylamino, for example methylamino, di-lower alkylamino, for example dimethylamino, acylamino, for example tert.-butoxycarbonylamino, or halogen, for example chlorine, bromine or iodine, it being possible for the substituent to be in any position in the aryl radical, for example in the o-, m- or ~-posi-tion of the phenyl radical, and it also being possible for the aryl radical to be polysubstituted by the same or different substituents.

Aryl-lower alkyl Ra has, for example, from 7 to 15 carbon atoms and con- ;
tains, for example, an unsubstituted or substituted, optionally branched ~;
radical mentioned under lower alkyl Ra and an unsubstituted or substi~
tuted radical mentioned under aryl Ra or Rb. Such an aryl-lower alkyl ``
rad~cal is, for example, benzyl, lower alkylbenzyl, such as 4-methyl- ~-benzyl, biphenylylmethyl, such as 4-biphenylylmethyl, lower alkoxybenzyl, such as 4-methoxybenzyl, 2-phenylethyl, 2-(~-hydroxyphenyl)-ethyl, ;~
diphenylmethyl, di-(4-methoxyphenyl)-methyl, trityl or - or ~-naphthyl-methyl. ~

Aryl lower alkenyl Ra has, for example, from 8 to 16 carbon atoms and ;- .
contains, for example, an unaubstituted or substituted radical mentioned under lower alkenyl Ra and an unsubstituted or substituted radical ~-mentioned under aryl Ra or R . Such an aryl-lower alkenyl radical is, for ~ ~;
example, styryl, 3-phenylallyl, 2-(-naphthyl)-vinyl or 2-(~-naphthyl)-vinyl.
.; ~ ..:
Vnsubstituted or substituted heteroaryl R or R is mono-, bi- or tri-cyclic and contains one or two nitrogen atoms and/or an oxygen or sulfur atom. R or Rb is, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, ~ ;~
quinolyl, isoquinolyl, quinoxalinyl, ~-carbolinyl or a benzo-fused or cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals.
This heterocycle may be partially saturated and, at a nitrogen atom, it -may be substituted by oxido, lower alky], for example methyl or ethyl, 21~0~

phenyl, or phenyl-lower alkyl, for example benzyl, and/or, at one or more carbon atoms, it may be substituted by lower alkyl, for example methyl, phenyl, phenyl-lower alkyl, for example benzyl, halogen, for example chlorine, hydroxy, lower alkoxy, for example m~thoxy, phenyl-lower alkoxy, for example benzyloxy, or by oxo, and is, for example, 2- or 3-pyrrolyl, phenylpyrrolyl, for example 4-- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methyl-:imidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3-or 4-pyridyl, 1-oxido-2-, -3- or -4-pyridinio, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example l-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-iso-quinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzo-furanyl, 2-bsnzoxazolyl, 2-benzothiazolyl, benz[e]indol-2-yl or ~-carbolin-3-yl.

Heteroaryl-lowsr alkyl R contains, for example, an unsubstituted or substituted radical mentioned under lower alkyl Ra and an unsubstituted or substituted radical mentioned under heteroaryl Ra or Rb and is, for example, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylmethyl, 2-(2-, 3-or 4-pyridyl~-ethyl, 4-imidazolylmethyl, 2-(4-imidazolyl)-ethyl, ~- or 3-indolylmethyl, 2-(3-indolyl)-ethyl or 2-quinolylmethyl.

Hydroxy Ra is unsubstituted or substituted, for example, by lower alkyl or aryl and is, for example, hydroxy, methoxy, ethoxy, n-butoxy, phenoxy, 4-hydroxyphenoxy or 3,4-methylenedioxyphenoxy.

Amino R is unsubstituted or substituted by one or two lower alkyl groups or by aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl or aryl- -methoxycarbonyl or is part of a five- or six-membered heterocycle con-taining one or two nitrogen atoms and, if desired, an oxygen or sulfur atom and is, for example, amino, methylamino, ethylamino, isopropylamino, n-bueylam1no, dimethylamlno, diethyla:ino, benzylamino, acetylam1no, ... . . . . .. . . . .

337 : ~
_ 19 _ pivaloylamino, methoxy-, ethoxy- or tert.-butoxy-carbonylamino, benzyl-oxycarbonylamino, l-pyrrolidinyl, l-pipericlinyl, l-methyl-4-pyridazinyl, 4-morpholinyl or 4-thiomorpholinyl.

A bivalent radical Q , which is an isostere of a dipeptide, is a radical in which the dipeptide atom sequence of the formula ~~-¢~ -¢-~
1 2 3 4 5 6 ~ ~ ~

is so modified at any desired site that the ability of the central amide bond to be hydrolysed is greatly reduced. In the context of this inven~
tion, ability to be hydrolysed is greatly reduced when the resulting ;~
compound of the formula I exhibits inhibitory action in the concentration ~;
ranges indicated hereinbefore against gag protease. Reduction of ability to be hydrolysed can be achieved by lengthening the chain to more than six atoms, shortening the chain to less than six atoms and/or by modify-ing one or more of the six atoms of the dipeptide atom sequence of the formula II.

Examples of suitable radicals Q are afforded by the following formulae in which the positions 3 to 5 of the formula II, that is to say, the partial structura ¢~

are varied as follows while preserving the terminal positions 1 and 2 as wall as 6~

_¢_~_ (IIa) -~-¢-~-O-¢-~- (IIb) -~-¢-~-¢-¢-~- (IIc) i ;2Q~?~337 ¢--~H--¢--¢--8-- ( IId) ~ ¢--8H ¢--~-- ( I I e ) --1~-¢--~H--¢--¢--~-- (IIf) --~--¢--~H--¢--1~-- ~ I I g ) ~1--¢--~H--¢--1~--¢--~-- ( IIh) --~--¢--~--¢--¢--8-- ( I I i ) --~--¢--¢--¢--¢--~-- ( I I j ) ¢ ¢ ~¢ 13 (IIk) ~ ¢--¢ -S ¢ l~ t I I 1 ) --1~--¢--¢--~--¢--1~ (IIm) _~_¢_~ _¢_~_ (IIn) --1~--¢--~¢--¢--~-- ( I I o ) --~--¢--~¢--1~ (IIp) gH ¢ (IIq) ~H ¢ ( I I r ) 2C3~ 37 wherein free valencies that are not bonded to M N or M C are, independ- ;
ently of one another, satisfied by hydrogen or by a radical of the Ra type, such as defined above in connection with R2, and/or free valencies .
at adjacent N and C atoms are bridged by lower alkylene having, for example, from 2 to 5 carbon atoms. Such isosteres are already known in principle; for example, they are described in European Patent Applica-tions 156 322 and 273 696.

Preferred isosteres Q are those of the formulae IIa to IIr in which the -free valencies that are not bonded to AAN or AAC are so satisfied by hydrogen or by radicals Ra and/or bridged by lower alkylene that the ~:
resulting isosteres correspond to dipeptide radicals, such as leucine- ::
valine, phenylalanine-valine, cyclohexylalanine-valine, leucine-alanine, cyclohexylalanine-alanine, leucine-glycine, cyclohexylalanine-glycine, : :~
tyrosine-proline, phenylalanine-proline or cyclohexylalanine-proline, ospecially to the dipeptide fragments leucine-valine or cyclohexyl-alanine-valine. ;~
:' Salts are especially the pharmaccutically acceptable non-toxic salts of :~
compounds of the formula I. ~

Such salts are formed, for example, by compounds of the formula I having ~ :
an acidic group, for example a carboxy group, and are, especially, `~ ~:
suitable alkali metal salts, for example sodium or potassium salts, or ~ :
suitable alkaline earth metal salts, for example magnesium or calcium salts, and also zinc salts or ammonium salts, and also those salts which are formed with organic amines, such as unsubstituted or hydroxy-substi- : ~:
tuted mono-, di- or tri-alkylamines, for example diethylamine, di-(2-hydroxyethyl)-amine, triethylamine, N,N-dimethyl-N-(2-hydroxyethyl)-amine, tri-(2-hydroxyethyl)-amine or N-methyl-D-glucamine. The compounds of the formula I having a basic group, for example an amino group, can form acid addition salts, for example with inorganic acids, ~or example :`~-hydrochloric acid, sulfuric acid or phosphoric acid, or with organic , carboxylic, sulfonic or sulfo acids, for example acetic acid, propionic ::
acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, `

', ~

ZC~ 3~7 methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, ~-amino-salicylic acid, 2-phenoxybenzoic acid, 2-ace~oxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, and with amino acids, such as, for example, the ~-amino acids mentioned hereinbefore, and also with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid, or with other acidic organic com-pounds, such as ascorbic acid. Compounds of the formula I having acidic and basic groups can also form internal salts.

For the purposes of isolation or purification it is also possible to use pharmaceutically unsuitable salts.

Compounds of the renin inhibitor type, such as, especially, compounds of the formula I, exhibit gag protease inhibiting effects. In particular, at , concentrations as low as the nanomolar range, they inhibit the action of gag proteases of HIV-1 and HIV-2 and are therefore suitable as agents against diseases caused by retroviruses, such as, for example, against AIDS.

The ability of the compounds of the formula I to inhibit the proteolytic activity o, for example, HIV-1 protease can be demonstrated, for example, in accordance with the method described by J. Hansen et al., The EMBO Journal 7, 1785-1791 ~1988). The inhibition of the action of gag protease is measured on a substrate that is a fusion protein, expressed -in E. coli, of the gag precursor protein and MS-2. The substrate and its cleavage products are separated by polyacrylamide gel electrophoresis and rendered visible by immunoblotting with monoclonal antibodies to MS-2.

In a test that is even easier to use and that permits exact quantitative statements to be made, a synthetic icosapeptide that corresponds to the cleavage site of the gag precursor protein is used as the substrate for the gag protease. This substrate and its cleavage products can be ,i. :. ~ .

- 2{~337 measured by high pressure liquid chromatography (HPLC). In this test, compounds of the present invention exhibit inhibitory effects at con- -centrations of 10 mol/l.
:' In another test, it is possible to demonstrate that the compounds of the present invention protect cells that are usually infected by HIV against such infection or at least retard such infection. In this test, the human ~-T-cell leukaemia cell line MT-2 (Science 229, 563 (1985)), which is extremely sensitive to the cytopathogenic effect of HIV, is incubated with HIV only or with HIV in the presence of the compounds according to -~
the invention and after a few days the viability of the cells so treated ~ -~
is evaluated. Compounds according to the invention exhibit infection-inhibiting effects at concentrations of 10 5 mol/l.
, Specific compounds, the use of which as gag protease inhibitors is pre-ferred, can be found in the Europenn Patent Applications mentioned at the beginning. The preferred compounds mentioned therein are preferred in the case of the present invention also. This is especially true of the com-pounds that are disclosed in European Patont Applications 143 746, 144 290, 184 550 and 236 734.

Preferred compouncls of the formula I have two or more c~-amino acid re-sidues in the radical AAN, or the radical AAN consists of only one -amino acid residue and at the same time the radical R2 is an analogue of phenylalanyl (H-Phe-) and/or they have two -amino acid residues in ~
the radical AAC, or the radical AAC consists of only one -amino acid -residue and at the same time the radical Rl is an analogue of the residue, bonded vla the nitrogen, of the amino acid tyrosine (-Tyr-OH).

' ' "'' ~
'', ,'"~ '.;
~`'~ "','`'' '.
;'' "'~ ' b~ ; . " " : ~; , .,, : " , , , , , , : . . ~ ' - .

` ` 2C~lCi5~337 A radical R2 that may be regarded as an analogue of phenylalanyl has t~e structural element of the formula ~- .
ç/ 1 C3 ( Ib) '! ~! ~ -wherein the carbocyclic ring may also be completely or partially saturated, one of the carbon atoms of the carbocyclic ring may be linked to C2 or C3 to ~orm a preferably five- or six membered ring, one of the carbon atoms C2 and C3 may have been replaced by a hetero group or atom, such as NH, O or S, thc carbonyl group may be a heterocarbonyl group, such as P=O, and free valencies carry hydrogen or substituents, for example lower alkyl, lower alkylthio-lower alkyl, lower alkylsulfinyl-lower alkyl, lower alkylsulfonyl-lower alkyl, phenyl-lower alkyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, amino-lower alkyl, lower alkylamino-lower alkyl, lower alkanoylamino-lower alkyl, lower alkanoyl, lower alkanoyl-lower alkyl or lower alkylcarbamoyl, these substituents preferably being at Cz.

A completely or partially saturated carbocyclic ring is in this connec-tion, for example, cyclohexyl or cyclohexenyl. Five- or six-membered rings in the sense of the above paragraph are, for example, phenyl, cyclohexyl, pyrrolyl, pyranyl, dihydropyranyl or thio analogues of the mentioned heterocyclyl radicals. These definitions also apply to the radicals Rl described below that are analogous to tyrosine.

Such analogues R2 are, for example, 3~phenyl- or 3-cyclohexyl-propionyl which may be substituted, especially in the 2-position, by substituents of the type: lower alkyl, such as methyl, ethyl or tert.-butyl, lower alkylthio-lower alkyl, such as tert.-butylthiomethyl, lower alkylsul-finyl-lower alkyl, such as tert.-butylsulfinylmethyl, lower alkylsul- -~
fonyl-lower alkyl, such as tert.-butylsulfonylmethyl, phenyl-lower alkyl~
such as benzyl, hydroxy, lower alkoxy, such as methoxy, phenyl-lower .. . .

alkoxy, such as benzyloxy, amino-lower alkyl, such as aminomethyl or 2-amino-2-propyl, lower alkylamino-lower alkyl, such as methylamino-methyl, lower alkanoylamino-lower alkyl, such as acetylaminomethyl, lower alkanoyl, such as acetyl, lower alkanoyl-lower alkyl, such as acetyl-methyl, isobutyrylmethyl or pivaloylmethyl, or lower alkylcarbamoyl, such as methylcarbamoyl, or such analogues R2 are, for example, 2-naphthyl-carbonyl or hydrogenated forms thereof, such as, for example, 2-deca-hydronaphthylcarbonyl, 2-(3-indolyl)-acetyl or 2-(3-benzofuranyl)-acetyl, 3-chroman- or 3-thiochroman-carbonyl, or dibenzyloxyphosphoryl. -A radical Rl that may be regarded as an analogue of the residue, bondedvia the nitrogen, of the amino acid tyrosine has the structural element of the formula ~ (C) ~ (Ic) ~ ;

wherein the carbocyclic ring may contain a hetero atom, such as nitrogen, and may also be completaly or partially saturated and/or substituted, Eor ;;`~
e~amplo by hydroxy or by phenyl, the index v is O to 5, for example O to 3, one of the carbon atoms of the carbocyclic ring may be bonded to one oE the atoms -(C) - to form a preferably five- or six-membered ring and ' free valencies carry hydrogen or substituents, for example lower alkyl or hydroxy-lower alkyl. Such a radical Rl which may be regarded as an analogue of the residue of the amino acid tyrosine may also be lower ~ ~ ;
alkylamino. ~ ;

Such analogues Rl are, for example, butylamino, cyclohexylamino, 2-deca-hydronaphthylamino, 6-hydroxy-2-tetrahydronaphthylamino or 2-tetrahydro-naphthylamino, 6-hydroxy-2-naphthylamino or 2-naphthylamino, pyridyl-methylamino, phenyl- or hydroxyphenyl-lower alkylamino, such as 2-phenyl-or hydroxyphenyl-ethylamino or 5-phenyl- or hydroxyphenyl-pentylamino, l-hydroxymethyl-2-hydroxyphenylethylamino or biphenylyl-lower alkylamino, such as 4-biphenylylmethylamino. - --' . ;'-' ,`, 2C~5~37 Equally preferred are compounds of the formula I wherein Q is a radical of the partial formula ~H ¢ ¢ ~ (IId) -~-¢-8H - ¢-~- (IIe) or -~-¢-¢-~-¢-~- (IIm) wherein free valencies that are not bonded to AAN or AAC are, independ-ently of one another, satisfied by hydrogen, lower alkyl, aryl-lower alkyl or by cycloalkyl-lower alkyl and/or free valencies at adjacent N
and ~ atoms are bridged by lower alkylene. `~`

Especially preferred compounds of the formula I are those wherein Q is a radical of the partial formulae IId, IIe and IIm and free valencies are satisfied by such radicals that the resulting isosteres correspond to the dipoptide radicals leucine-valine, phenylalanine-valine, cyclohexyl-alanine-valine, leucine-glycine, cyclohexylalanine-glycine, tyrosine-proline, phenylalanine-prQline or cyclohexylalanine-proline.

The compounds the use of which as gag protease inhibitors is disclosed herein are known or can be prepared in a manner known per se, for example as described in the European Patent Applications already mentioned.

They are prepared, for example, by condensing a fragment of a compound of the formula I having a terminal carboxy group or a reactive acid derivative of that fragment with a fragment that is complementary to the compound of the formula I and has a free amino group or with a reactive derivative thereof having an activated amino group to form an amide bond, functional groups pr~sent in the reactants, with the exception of the ~
groups participating in the reaction, optionally being in protected form, -.
and, in an obtainable compound, removing any protecting groups present ~ ~:
and/or converting an obtainable compound of the formula I having a salt-forming group into its salt or converting an obtainable salt into the .~,~' ' , . . . ",. .. ...

2~C~S33~

free compound or into a different salt and/or optionally separating obtainable isomeric mixtures and/or, in an obtainable compound of the formula I, reversing the configuration of a chiral carbon atom and/or converting a compound of the formula I according to the invention into a ,.
different compound of the formula I according to the invention.
: :
The present invention relates also to the use of compounds of the renin inhibitor type, for example those of the formula I, in the manufacture of -pharmaceutical preparations for use as gag protease inhibitors, for example for combating diseases caused by retroviruses, for example AIDS.
For example, compounds of that type can be used for the manufacture of pharmaceutical preparations that contain an effective amount of those compounds together or in admixture with a significant amount of inorganic ; :
or organic, solid or liquid pharmaceutically acceptable carriers. The invention relates also to the said pharmaceutical preparations themselves for use as gag protease inhibitors or for combating diseases caused by retroviruses, for example AIDS. ~;
, ': ' The pharmaceutical preparations according to the invention are for enteral, such as nasal, rectal or oral, administration or for parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals) and contain an effective dose of the pharma-cological active ingredient on its own or together with a significant amount of a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, the body -weight, age and individual condition, on the disease to be treated and also on the mode of administration.
:. ,, The invention relates also to a method of treating diseases caused by retroviruses, for example AIDS, which comprises administering a thera-peutically effective amount of compounds of the renin inhibitor type, for example those of the formula I. The dosages to be administered to warm-blooded animals, for example humans of approximately 70 kg body weight, are from approximately 3 mg to approximately 3 g, preferably from approximately 10 mg to approximately 1.5 g, for example approximately .. . ~ . - , . . -.. . ., : -:, .: . . . , .. . : .... . ~ . - .. .:

r~, Z~ 3;~7 from 300 mg to 1000 mg, per person per day, divided into preferably from 1 to 3 single doses which may, for example, be of equal size. Children usually receive half the adult dose.

The pharmaceutical preparations contain from approximately 1 % to approximately 95 %, preferably from approximately 20 % to approximately 90 %, active ingredient. Pharmaceutical preparations according to the invention may, for example, be in dosage unit form, such as ampoules, phials, suppositories, dragées, tablets or capsules.

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

There are preferably used solutions of the active ingredient, and also suspensions, especially isotonic aqueous solutions or suspensions, it being possible, for example in the case of lyophilised preparations which contain the active ingredient on its own or together with a carrier, for example mannitol, to prepare these before use. The pharmaceutical pre-parations may be sterilised and/or contain adjuncts, for example pre-servativcs, stabili~ers, wetting agents and/or emulsifiers, solubilisers, salts Eor regulating the osmotic pressure and/or buffers, and are pre-pared in a manner known per se, for example by means of conventional dissolving or lyophilising processes. The solutions or suspensions mentioned may contain substances that increase the viscosity, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, poly-vinylpyrrolidone or gelatin.

Suspensions in oil contain as oily component the vegetable, synthetic or , semi-synthetic oils customary for injection purposes. There may be mentioned as such especially liquid fatty acid esters that contain as acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, such as, for example, lauric acid, tri-decylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids, such as, for example, oleic acid, elaidic acid, erucic '' '` ' -, ~.

,:''; ': ~':
: ~. - .~

2Q~33~7 acid, brassidic acid or linoleic acid. The alcohol component of these fatty acid esters has at most 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 their isomers, but especially glycol or glycerol. There may therefore be mentioned as -examples of fatty acid esters: ethyl oleate, isopropyl myristate, iso-propyl palmitate, "Labrafil M 2735" (polyoxyethylene glycerol trioleate manufactured by Gattefossé, Paris), "Myglyol 812" (triglyceride of saturated fatty acids of chain length C8 to Cl 2 ~ manufactured by Chemische Werke Witten/Ruhr, Germany), but especially vegetable oils, such as cotton seed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and, especially, groundnut oil. ;

The manufacture of the injection preparations is effected in customary manner under sterile conditions, as is the introduction thereof into ampoules or phials and ~he sealing of the containers.

Pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulat-ing a resulting mixture and, if desired or necessary after the addition of suitable ad~uncts, processing the mixture or granulate into tablets or dragee cores. They can also be incorporated into plastics carriers which release the active ingredients, or allow them to diffuse, in a controlled manner.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or -~
calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphase, also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or poly- -vinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinyl-pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as 5~337 magnesium stearate or calcium stearate, and/or polyethylene glycol.
Dragée cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solu-tions which may contain gum arabic, talc, polyvinylpyrrolidone, poly-ethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as ethylcellulose phtha:Late or hydroxypropylmethyl-cellulose phthalate. Colourings or pigments can be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient.

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

Temperatures are given in degrees Celsius. The Rf values are determinedon silica gel thin-layer plates in the following solvent systems:

A ethyl acetate/n-hexane 1:1 B othyl acetateln-hexane 1:2 C ethyl acetate/n-hexane 1:4 D ethyl acetate/n-hexane 1:6 ~
E ethyl acetate/n-hexane 1:9 ; ;
F methylene chloride/methanol 19:1 ;
G methylene .hloride/methanol 9:1 H methylene chloride/methanol 4:1 I methylene chloride/methanol/water300:10:1 J methylene chloride/ether 4:1 ~ ;~
K methylene chloride/methanol/conc. ammonia 40:10:1 L methylene chlorideimethanol/conc. ammonia 350:50:1 M methylene chloride/methanol/water/glacial acetic acid 150:54:10:1 N methylene chloride/methanol/water14: 6:1 0 chloroform/methanol/water/glacial acetic -~
acid 150:54:10:1 ',:'~ ' :.' , ., '' .

'''',,' , ; ~
'~

- z0~ 337 P chloroformtmethanol/water/glacial acetic acid 180:20:2:1 - -Q chloroformtmethanol/water/glacial acetic acid 170:26:3:1 R ethyl acetate S methylene chloride/methanol/conc. ammonia 800:50:1 -T methylene chloride/methanol/conc. ammonia 90:10:1 -U toluene/ethyl acetate 4:1 V ethyl acetate/methanol 1:1 W ethyl acetate/n-hexane 5:2 For example, the abbreviation "Rf(A)" denotes that the Rf value has been determined in system A. The ratio of the solvents to one another is given in parts by volume.

The same abbreviations are used for the eluant systems in the flash chro-matography and the medium-pressure chromatography.
, The retention times (tRet) in the high-pressure liquid chromatography (HPLC) are determined over a 250 x 4.6 mm reversed phased C1~ Nucleosil~
5 ~ column at a flow rate of 1 ml/min. Gradient A: 0 % ~ 100 % aceto-nitrile in water containing 0.05 % trifluoroacetic acid in 60 min.;
gradiant B: 10 % ) 100 % acetonitrile in water containing 0.05 % tri-fluoroacetic acid in 40 min.; gradient C: 0 % ~ 90 % acetonitrile in water containing 1 % trifluoroacetic acid in 30 min.. For example, the abbreviation "tRet(A)" denotes that the retention time has been determined with gradient A.

The values for proton nuclear magnetic resonance spectroscopy (lH-NMR) are given in ppm (parts per million) with reference to tetramethylsilane as the internal standard. s = singlet, d = doublet, t = triplet, ~-q = quartet, m = multiplet, dd a double doublet, br = broad. The values for infrared spectra (IR) are wave numbers in cm 1 In the fast atom bombardment mass spectrometry (FAB-MS), the values are given for the protonated mass (M~H) .

~,~ .,,., .,.. -. ,, . . .. , -. - .. - .. , . . ,, ., "- . . ..... , .. -, .. . . ..

211~0~337 The radical referred to as -ChaCVal- denotes the bivalent radical of (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropyl-hexanoic acid and has the formula ~H \-/
-~ s~ j(s) ./ \., o !, ,! .
: ' ., The radical referred to as -ChaCxVal- is derived from the radical -Cha-Val- by bridging NH and OH by an isopropylidene group and has the formula :.~': ,.'' :' I o~
T T
.,, ., ~ , .
\./ ~'', The radical rcferred to as -LeuCVal- accordingly denotes the bivalent `
radical of (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyl-octanoic ;;
acid. Sta is the bivalent radical of (3S,4S)-4-amino-3-hydroxy-6-methyl~
heptanoic acid, statin. ACHPA denotes the bivalent radical of (3S,4S)-4 amino-5-cyclohexyl-3-hydroxy-pentanoic acid. ;~
"
The radical referred to as -PheredPro- denotes the bivalent radical ; ~-~
of N-(2(S)-amino-3-phenyl-propyl)-L-proline and has the formula !: ' I ' . ~ ! ~, `.

T il .~ ~./- .- . .
'~;',"'.":~"`

.`'`:,'~

3~

Accordingly, -Cha dPro- denotes the bivalent radical of N-(2(S)-amino-3-cyclohexyl-propyl)-L-proline and -CharedVal-denotes the bivalent radical of N-(2(S)-amino-3-cyclohexyl-propyl)-L-valine.

The abbreviations conventionally used in peptide chemistry are used to refer to bivalent radicals of natural ~-amino acids. Tyrosine radicals that are etherified at the phenolic hydroxy group by the radical R are referred to as Tyr(OR). Nle denotes the radical of norleucine, Cha the radical of cyclohexylalanine.

Other abbreviations:
abs. = absolute (anhydrous) BBSP = 2(S)-benzyl-3-tert.-butylsulfonyl-propionyl BOC = tert.-butoxycarbonyl BOP = benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate b.p. = boiling point conc. = concentrated DMA = dimethylacetamide DCCI = dicyclohexylcarbodiimide DCU = dicyclohexylurea DMF = dimethylformamide DMSO ~ dimethyl sulEoxide Fmoc = 9-fluorenylmethoxycarbonyl HBTU = O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluoro-phosphate HOBH = N-hydroxy-endo-norbornane-2,3-dicarboxylic acid imide HOBt = l-hydroxybenzotriazole min. = minute(s) m.p. - melting point OtBu = tert.butyloxy Tcp = trichlorophenyl THF = tetrahydrofuran Z = benzyloxycarbonyl Example 1: Z-Arg-Ar~-Pro-Phe-Val-ChaCVal-Val-Tyr-OMe A mixture of 160 mg of H-Phe-Val-ChaCVal-Val-Tyr-OMe, 180 mg of Z-Arg-Arg-Pro-OH-HCl, 42 mg of triethylamine hydrochloride, 62 mg of DCCI, 42 mg of HOBt and 10 ml of DMF is stirred at room temperature for 48 hours. -~
The crystallised DCU is filtered off and the filtrate is concentrated by evaporation. The residue is dissolved in methanol and precipitated with diisopropyl ether. The crude product is then purified by flash chromato-graphy on 20 g of silica gel (eluant M~. Rf(M) = 0.25; FAB-MS:
(M~H) = 1337; tRet(A) = 35-2 min-The starting materials are prepared in the following manner:

a) 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propionic acid ethyl ester: `~ ~;
243 g of 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propionic acid (manu- ~`
facture: Helvetica Chimica Acta 57, 2131 (1974)) are placed in 600 ml of "
toluene and 900 ml of ethanol. The reaction mixture is cooled to 0 and -88.3 g of thionyl chloride are added dropwise within 30 minutes. The ;
cooling is removed and the mixture is stirred for 18 hours. The reaction ~
mixture is filtered and the filtrate is concentrated. The residue is ~;
separated by means of flash chromatography (2 kg of silica gel 60, 40-63 ~m, eluan~t E). The fractions containing the product are combined, concentrated by evaporation and dried under a high vacuum. The title compound is obtained in the form of a slightly yellowish oil.
Rf(E) = 0.2; Rf(B) = 0.52. ; ; ;~

b) 2(S)-benzyloxycarbonylamino-3- yclohexyl-propanal: 116.1 g of 2(S)- "
benzyloxycarbonylamino-3-cyclohexyl-propionic acid ethyl ester are placed in 2.2 litres of toluene and cooled to -65. 836 ml of diisobutylalu-minium hydride are added dropwise at -65 within 30 minutes and the mixture is then stirred for 20 minutes. Then 84.2 ml of methanol are added dropwise within 10 minutes at -65 and subsequently 825 ml of aqueous potassium sodium tartrate solution without cooling. The reaction mixture is discharged onto 3 litres of potassium sodium tartrate solu~
tion/ice and extracted with 5 litres of ether. The ethereal phase is washed with 2 litres of water, then immediately poured into a solution consisting of 106 g of semicarbazide hydrochloride and 156.5 g of sodium ;
; ~' ':, : .:

--; 20~ 337 acetate in 620 ml of water and 620 ml of ethanol. The reaction mixture is then stirred at room temperature for 1 hour and subsequently separated in a separating funnel, and the aqueous phase is extracted with 2 x 1.5 litres of ether. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The crude product is purified by means of flash chromatography (2 kg of silica gel 60, 40-63 ~m, eluant A). Con-centration by evaporation of the combined product-containing fractions yields the semicarbazone of the title compound, Rf(G) = 0.51. 130 g of this semicarbazone are dissolved in 1 litre of THF, and 282 ml of 37 %
formaldehyde solution and then, at 10, 143 ml of 0.5N HCl are added ;~
thereto. The reaction mixture is stirred at room temperature for 2 hours and is filtered, and the filtrate is washed with 0.5 litre of water, 0.5 litre of NaHC03 and 0.5 litre of water. The aqueous phases are extracted with 600 ml of ether. The ethereal phases are dried over magnesium sul-fate and concentrated by evaporation. 100 ml of toluene are added to the residue and the whole is concentrated by evaporation to yield the title compound. The latter is further processed immediately.

c) (l(S)-benzyloxycarbonylamino-2-cyclohexyl-ethyl)-oxirane: 18.9 g of sodium hydride dispersion (55 % in oil) are freed of oil in a dry sul-fonating flask under argon by stirring three times in 50 ml of petroleum ether (b.p. 40-60) and subsequently decanting off the solvent each time.
After drying under a high vacuum, a grey powder is obtained which is placed in 500 ml of THF; 55.6 g of trimethylsulfoxonium iodide are added thereto, the temperature increasing to approximately 40. The grey suspension is boiled under reflux for 1 hour and then, within a period of 50 minutes at -70, a solution of 108.6 g of 2(S)-benzyloxycarbonylamino-3-cyclohexyl-propanal in 250 ml of THF is added. The yellow suspension is stirred at 0 for 2 hours. The yellowish turbid solution is poured onto 500 g of ice. The aqueous solution is extracted with 2.5 litres of ether, and the organic phase is washed with water and, after being dried over sodium sulfate, is concentrated by evaporation. The oily residue is separated by means of flash chromatography (2.5 kg of silica gel 60, 40-63 ~m, eluant C). The fractions containing the product are combined, , ';' ':'. .' .' ,. . ' ., ' . ' . ' , . . ~ ., , ' , : ' 2~

concentrated by evaporation and dried under a high vacuum. The title compound (diastereoisomeric mixture, approximately 4:1) is obtained in the form of a slightly yellowish oil. Rf(I) = 0.71; Rf(C) = 0.16.

d) 3(S)-benzyloxycarbonylamino-4-cyclohexyl-1-iodo-butan-2(R,S)-ol:
42.3 g of (l(S)-benzyloxycarbonylamino-2-cyclohexyl-ethyl)-oxirane are taken up in 200 ml of acetonitrile and the resulting solution is cooled to 0. After the addition of 20.9 g of sodium iodide, there are added dropwise at 0, over a period of 30 minutes, 17.7 ml of trimethylchloro-silane~ The mixture is stirred at 0 to 3 for 40 minutes and then poured into 700 ml of ice-cold water. The aqueous mixture is extracted with ~ ;
ether and the organic phase is washed with 750 ml of a 5 % aqueous sodium thiosulfate solution and 750 ml of saturated, aqueous sodium chloride solution. After drying over sodium sulfate and concentrating by evapora-tion, an oily mixture of the title compound is obtained which is further `~ ~ `
processed directly. `

e) 3-benzyloxycarbonyl-4(S)-cyclohexYlmethYl-2,2-dimethyl-5(R)-iodo-methyl-1,3-oxazolidine: 49.3 g of the compound of Example 1 d) and 1.07 g of ~-toluenesulfonic acid monohydrate are stirred in 140 ml of 2,2-di-methoxypropane and 450 ml of methylene chloride for 3 hours at room tem-perature. The mixture is extracted by shaking between l litre of methylene chloride and 500 ml of saturated, aqueous sodium hydrogen car-bonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by means of flash chromatography (3 kg of silica gel 60, 40-63 ~m, eluant D). Concentration by evaporation of the purified, product-containing fractions yields the title compound in the form of a slightly yellowish oil. Rf~C) = 0.55; Rf(D) = 0.46.

f) 2(R,S)~~3-benzyloxycarbonyl-4(S)-cyclohexYlmethyl-2,2-dimethyl-1,3-oxazolidinyl-5(S)-methyl)-3-methyl-butyric acid methYl ester: 14.3 ml of diisopropylamine are dissolved under argon in 200 ml of absolute tetra-hydrofuran and cooled to 0. Then, at 0 to 5, 65.8 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise to the mixture over a period of 20 minutes and the whole is stirred for 20 minutes. Then, at ;: .: , .
.'' ''' .

33~ :

~ 37 - !

from -70 to -75, 13.3 ml of isovaleric acid methyl ester are added dropwise and the mixture is stirred for 1.5 hours at -75. At from -60 to -75, 320 ml of hexamethylphosphoric acid triamide are added dropwise while stirring. The resulting suspension is stirred for 10 minutes and, finally, at from -70 to -75, a solution of 43.4 g of the compound of Example 1 e) in 110 ml of tetrahydrofuran is added dropwise in 5 minutes.
The reaction mixture is stirred at room temperature for 2.5 hours and finally poured onto a mixture of l litre of saturated, aqueous ammonium chloride solution and 500 g of ice. The aqueous phase is extracted with 2 litres of ethyl acetate, and the organic phase is washed with water and dried over sodium sulfate. After concentration by evaporation, the diastereoisomeric mixture of the title compound is obtained in the form of a yellow oil. Rf(C) = 0.36; Rf(E) = 0.21 (values for the less polar component).

g) 2~R,S)-(3-benzyloxycarbonyl-4(S)-cYclohexylmethyl-2,2-dimethyl-1,3-oxazolidinyl-5(S)-methyl)-3-methyl-butyric acid: 1.77 ml of water are added at approximately 5 to 16.5 g of potassium tert.-butanolate in 250 ml of ether. The white suspension is stirred in an ice ba~h for a further 10 minutes and then 35.ô g of the compound of Example 1 f) (diasterqoisomeric mixture) in 250 ml of ether are added thereto, the temperature being maintained below 10. The reaction mixture is then stirred at room temperature for 18 hours and finally poured into 500 ml of saturated, aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with saturated, aqueous sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The oily crude product is separated by flash chromatography (2.5 kg of silica gel 60, 40-63 ~m, eluant C).
Z-ChaCxVal-OH, the less polar component of the title compound having the desired configuration of the carbon atom bonded to the isopropyl group (S-configuration), is obtained in the form of a yellow oil. Rf(I) =
0.20; Rf(J) = 0.35.

`:-` Z~)~35~3~7 h) HCl-H-Val-Tyr-OMe: 10.0 g of Z-Val-Tyr-OMe are hydrogenated under normal pressure and at room temperature in 200 ml of methanol and 24 ml of lN HCl in the presence of 1.0 g of palladium-on-carbon (10 % Pd) until saturation is reached. The reaction mixture is filtered, and the filtrate is concentrated by evaporation and dried. Rf(N) = 0.64. ;~

i) Z-Cha -Val-Val-Tyr-OMe: A mixture of 2.06 g of HCl-H-Val-Tyr-OMe, 3.12 g of Z-Cha XVal OH, 1.74 g of DCCI, 1.22 g of HOBt, 0.75 g of N-methylmorpholine and 50 ml of DMF is stirred at room temperature for 16 hours. The DC~ is filtered off, and the filtrate is concentrated and dried under a high vacuum. The residue is purified by means of flash chromatography (100 g of silica gel 60, eluant B). Rf(A) = 0.36. ~ ;

j) H-Cha-Val-Val-Tyr-OMe: 3.6 g of Z-Cha -Val-Val-Tyr-OMe are hydrogenated under normal pressure and at room temperature in 80 ml of ~`methanol/water 9:1 in the presence of 360 mg of palladium-on-carbon (10 % Pd) until saturation is reached. The reaction mixture is filtered, -and the filtrate is diluted with 30 ml of water and stirred at room temperature for 5 hours. After evaporating off the solvent, the title compound is lyophilised from dioxane/water 9:1. Rf(H) = 0.10.

k) BOC-Val-Cha-Val-Val-Tyr-OMe is obtained analogously to Example 1 i) ~-starting from 1.45 g of H-Cha-Val-Val-Tyr-OMe, 630 mg of BOC-Val-OH, -~;
530 mg of HOBH and 66Q mg of DCCI, and is purified by re-precipitation from methanol/NaHCO3 solution. Rf(G) = 0.75.

1) HCl-H-Val-Cha-Val-Val-Tyr-OMe: 2.16 g of BOC-Val-Cha-Val-Val-Tyr OMe are dissolved in 20 ml of 4.3N HCl in dioxane and the whole is stirred at room temperature for 30 minutes. The reaction mixture is con-centrated by evaporation, and the residue is purified by flash chromato-graphy (60 g of silica gel 60, eluant G). Rf(G) = 0.18.
;: :.': ,: ' ' .
m) Fmoc-Phe-Val-Cha-Val-Val-Tyr-OMe: A mixture of 240 mg of HCl-H-Val-Cha-Val-Val-Tyr-OMe, 170 mg of Fmoc-Phe-OTcp, 0.15 ml of N-ethyldiiso-propylamine and 10 ml of DMF is stirred at room temperature for 20 hours.
' '' ' .

3~

The reaction mixture is concentrated by evaporation, and the residue isprecipitated with 100 ml of diisopropyl ether. The precipitate is filtered off and then lyophilised from dioxane/water 9:1.

n) H-Phe-Val-ChaCVal-Val-Tyr-OMe: A solution of 305 mg of Fmoc-Phe-Val-Cha-Val-Val-Tyr-OMe, 5 ml of piperidine and 5 ml of DMF is stirred at room temperature for 60 minutes and then concentrated by evaporation. The residue is dissolved in a small amount of methylene chloride and precipi-tated with diisopropyl ether. The precipitate is filtered off at 0 and then lyophilised from dioxane/water 9:1. Rf(M) = 0.7.

Example 2: BBSP-Val-Cha-Val-Val-TYr-OMe Analogously to Example 1, the title compound is prepared from 760 mg of HCl-H-Val-Cha-Val-Val-Tyr-OMe (Example 1 l), 350 mg of 2(S)-benzyl-3-tert.-butylsulfonylpropionic acid (BBSP-OH), 190 mg of HOBt and 280 mg of DCCI, and is purified by flash chromatography. Rf(G) = 0.50; FAB-MS:
(M+H) = 913; tRet(A) = 42-1 min.

The starting material is prepared as follows:

a) 2(S)-benzyl-3-tert.-butylsulfon~_ propionic acid (BBSP-OH): 142 g of 2(R,S)-benzyl-3-tert.-butylsulfonyl-propionic acid are reacted with 85.7 g of (+)-dehydroabietylamine and 27.8 ml of triethylamine in 2 litres of isopropanol. After crystallisation of the salt four times from hot isopropanol, the acid is freed again by extraction with dilute sodium carbonate solution followed by acidification with dilute hydro-chloric acid. Recrystallisation from ethyl acetate/hexane yields the title compound in a high degree of optical purity (over 98 % ee):
[~] = -10.9 (c = 0.91 in CH2Cl2); m.p. 99-101; Rf(A) = 0.16;
D , Rf(B) = 0.4.

b) 2(R,S)-benzyl-3-tert.-butylsulfonyl-propionic acid: 91.9 g of 2-benzyl-3-tert.-butylsulfonyl-propionic acid ethyl ester are boiled under reflux for 15 hours in 500 ml of 6N hydrochloric acid and 100 ml of acetic acid. ~pon cooling, the title compound crystallises directly out Z0~37 of the reaction mixture. M.p. 147-8; Rf(~) = 0.4; 1H-NMR (CDC13): 1.35 (s, 9H), 2.97 (m, lH), 3.05 (dd, lH), 3.22 (dd, lH), 3.45 (m, 2H), 7.25 -(m, SH); 8.5 (br s, lH). -c) 2-benzyl-3-tert.-butylsulfonyl-propionic acid ethyl ester: 60 g of ~-benzylacrylic acid ethyl ester are dissolved in 600 ml of ethanol and reacted with 0.83 g of sodium methanolate and 37 ml of tert.-butylmer-captan. The mixture is stirred at room temperature for 24 hours, diluted with 500 ml of 0.04N aqueous sulfuric acid and, while cooling with ice, 260 g of Oxone~ (potassium peroxomonosulfate, 50 % KHSOs, Ventron) are added thereto. The reaction mixture is stir}ed overnight at room tem-perature, then filtered and concentrated. The aqueous solution is ;
extracted with methylene chloride, and the extracts are dried over sodium sulfate and concentrated by evaporation. M.p. 47-48; lH-NMR (CDCl3): ;
1.13 ppm ~t, 3H), 1.38 (s, 9H), 2.95 (dd, lH), 3.01 (dd, lH), 3.10 (dd, lH), 3.42 (dd, lH), 3.46 (dd, lH), 4.12 (q, 2H), 7.25 (m, 5H).

d) ~-benzylacrylic _cid ethyl ester- 4.0 g of KOH in 50 ml of ethanol are added a~ room temperature to 20 g of benzylmalonic acid diethyl ester in 40 ml of ethanol, and the reaction mixtur0 is stirred overnight at room `;
temperature, concentr~ted by evaporation, 7.1 ml of water are added thereto and the whole is acidified in an ice bath with 6.3 ml of conc.
hydrochloric acid. The reaction mixture is partitioned between water and ether, and the organic phase is dried and the ether is distilled off.
12.9 ml of pyridine, 0.61 g of piperidine and 1.78 g of paraformaldehyde are added to the residue. The mixture is heated for 90 minutes in an oil bath ~130), cooled, 220 ml of water are added thereto and the whole is extracted three times with 75 ml of n-hexane. The combined organic phases ;~
are washed with water, lN HCl, water, saturated NaHCO3 solution and brine. The title compound is obtained by distillation. lH-NMR (DMSO-d~
1.2 ppm (t, 3H), 3.6 (d, 2H), 4.1 (q, 2H), 5.6 (m, lH), 6.15 (m, lH), -7.25 (m, 5H).
:" :~:

-. ~ ZQ~337 Example 3: BBSP-Val-Cha-Val-Val-Tyr-OH
A mixture of 65 mg of BBSP-Val-Cha-Val-Val-Tyr-OMe (Example 2), 2 ml of 2N NaOH and 3 ml of dioxane is stirred at room temperature for 20 minutes. The reaction mixture is then diluted with 2 ml of 2N HCl and lyophilised. The residue is purified by means of flash chromatography (8 g of silica gel, eluant H). Rf(N) = 0.53.

Example 4: BBSP-Val-Cha-Val-Val-Tyr-NH2 ~nalogously to Example 2, the title compound is prepared from 30 mg of HCl-H-Val-ChaCVal Val-Tyr-NH2, 15 mg of 2(S)-benzyl-3-tert.-butylsul-fonyl-propionic acid (BBSP-OH), ~ mg of HOBt and 12 mg of DCCI and is purified by flash chromatography on 7 g of silica gel 60 (eluant F).
Rf(G) = 0.32; FAB-MS: (M~H) = 898; tRet(A) = 41-7 min-The starting materials are prepared in the following manner:

a) HCl-H-Val-Cha-Val-Val-Tyr-NH2 is prepared analogously to Example 1 l) from 360 mg of BOC-Val-Cha-Val-Val-Tyr-NH2 and 5.0 ml of 4.3N HCl in dioxane. Rf (L) = 0.3.

b) BOC-Val-ChaCVal-Val-Tyr-NH2 is obtained analogously to Example 1 k) from 300 mg of H-Cha-Val-Val-Tyr-NH2, 147 mg of BOC-Val-OH, 122 mg of HOBH and 268 mg of DCCI. Rf(G) = 0.33.

c) H-Cha-Val-Val-Tyr-NHz is obtained analogously to Example 1 ;) by hydrogenating 600 mg of Z-ChaCxVal-Val-Tyr-NHz in the presence of 60 mg of palladium-on-carbon (10 % Pd). Rf(L) = 0.06.

d) Z-Cha XVa1~ yr~2: A mixture of 772 mg of Z-ChaCxVal-Val-Tyr-OH, 590 mg of NH4Cl, 315 mg of DCCI, 217 mg of HOBt and 10 ml of DMF
is adjusted to pH 5.5-6.0 with NaHCO3 and then stirred for 16 hours. The DCU is filtered off and the filtrate is concentrated by evaporation. The residue is purified by flash chromatography on 40 g of silica gel 60 (eluant F). Rf(G) = 0.40.

2~1a!i:i~37 e) Z-Cha - Val-Val-Tyr-OH is prepared analogously to Example 3 from 790 mg of Z-Cha XVal-Val-Tyr-OMe (Example 1 i)), 4 ml of 4N NaOH and 16 ml of dioxane. Rf(G) = 0.07.
xample 5: N-(3-amino-3,3-dimethylpropanoyl)-TYr(OMe)-Val-ChaCVal-Val-Tyr-NH 2 A solution of 120 mg of N-(3-tert.-butoxycarbonylamino-3,3-dimethylpro-panoyl)-Tyr(OMe)-Val-Cha-Val-Val-Tyr-NH2 in 1~0 ml of 95 % aqueous trifluoroacetic acid is stirred for 20 minutes. The reaction mixture is concentrated by evaporation and the residue is purified by flash chroma-tography on 10 g of silica gel 60 (eluant G). Rf(L) = 0.06, Rf(K) = 0.46;
FAB-MS: (M+H) = 908; tRet(A) = 35-6 min-The starting materials are prepared in the following manner: ;

a) N-(3-tert.-butoxycarbonylamino-~ 3-dimethylpropanoyl)-Tyr(OMe)-Val-Cha -Val-Val-Tyr-NH2 is prepared analogously to Example 1 i) from 90 mg of H-Tyr(OMe)-Val-ChaCVal-Val-Tyr-NH2, 31 mg of 3-tert.-butoxycarbonyl-amino-3,3-dimethylpropionic acid, 26 mg of HOBt and 34 mg of nCCI and is purified by flash chromatography on ô g of silica gel 60 (eluant Rf(G) = 0.30.
.: . :
b) ~I-Tyr(OMe)-Val-ChaCVal-Val-Tyr-NH2 is prepared analogously to Examples 1 m) and 1 n) fro~ 260 mg of HCl~H-Val-Cha-Val-Val-Tyr-NH2 (Example 4a)), 320 mg of Fmoc-Tyr(OMe)-OTcp and 0.15 ml of N-ethyldiiso-propylamine.

c) Fmoc-Tyr_OMe)-OTcp: 0.76 g of trichlorophenol and 0.82 g of DCCI are added at 0 to a solution of 1.45 g of Fmoc-Tyr(OMe)-OH in 30 ml of abs. ~`
THF, and the reaction mixture is stirred for ~ hour at 0 and then for 2 hours at room tempe-rature. The DCU is filtered off at 0, the filtrate --is concentrated by evaporation and the residue is crystallised from ~-THF/hexane.

~2~0~37 Example 6- Z-Ar~-Ar~-Pro-Tyr(OMe)-Val-Cha-Val-Val-Tyr-NHz Analogously to Example 1, the title compound is prepared from 150 mg of H-Tyr(OMe)-Val-Cha-Val-Val-Tyr-NHz, 150 mg of Z-Arg-Arg-Pro-OH-HCl, 35 mg of triethylammonium chloride, 50 mg of HOBt and 68 mg of DCCI.
Rf(M) = 0.24; tRet(A~ = 36-3 min-xample 7: N 2(R,S)-benzyl-3-pivaloyl-propionyl)-Nle-Cha-Val-Val-Tyr-OMe A solution of 20 mg of HCl-H-Nle-Cha-Val-Val-Tyr-OMe, 22 mg of (R,S)-2-benzyl-3-pivaloylpropionic acid (J. Med. Chem. 31, 1839 (1988)), 33 mg of HBTU and 24 ~l of triethylamine in 2 ml of DMF is stirred at room tem-perature for 2 hours. The mixture is completely concentrated by evapora-tion, and the residue is washed with saturated sodium bicarbonate solu-tion and diisopropyl ether and finally dissolved in DMF. The product is precipitated with diisopropyl ether and, after lyophilisation from dioxane/tert.-butanol/water, yields the title compound in the form of a diastereoisomeric mixture. FAB-MS: (M+H) = 891; Rf(P) = 0.55; HPLC: 2 diastereoisomers in a ratio of 1.8:1, tRet(B) = 30.0 and 30.4 min.
he starting material is prepared in tho following manner:

a) _l H-Nle-Cha-Yal-Val-Tyr-OMe is prepared analogously to Example 1 l~ from 50 mg of BOC-Nle-Cha-Val-Val-Tyr-OMe and 5 ml of 4N HCl in dioxane. The product is lyophilised from dioxane. Rf(P) = 0.15;
tR t(B) = 19.9 min.

b) BOC-Nle-Cha-Val-Val-T~r-OMe: A solution of 60 mg of H-Cha-Val-Val-Tyr-OMe (Example 1 j)), 28 mg of BOC-Nle-OH, 46 mg of HBTU and 35 ~l of triethylamine in 2 ml of DMF is stirred at room temperature for 3 hours.
The mixture is concentrated by evaporation, and the residue is washed with saturated sodium bicarbonate solution and diisopropyl ether and finally dissolved in DMF. The product is precipitated with diisopropyl ether and lyophilised from dioxane/tert.-butanol/water. FAB-MS:
(M+H) = 761; Rf(P) = 0.50; tR (B) = 27.9 min.

' ' .

: zo~ j3~7 :

:~, '.:
Example 8: BBSP-Nle-Cha-Val-Val-Tyr-OMe Analogously to Example 7, the title compound is prepared from 20 mg of HCl-H-Nle-Cha-Val-Val-Tyr-OMe (Example 7 a)), 25 mg of 2(S)-benzyl-3-tert.-butylsulfonylpropionic acid (BBSP-OH), 33 mg of HBTU and 24 ~1 of triethylamine, is purified by flash chromatography on 10 g of silica gel (eluant P) and lyophilised from dioxane/tert.-butanol/water. FAB-MS:
(M-~H) = 927; Rf(P) = 0.46; tRet(B) = 28.0 min- ~
:.: . ' Example 9: BBSP-Tyr-Cha-Val-Val-Tyr-OMe A solution of 17 mg of BBSP-Tyr(OtBu)-Cha-Val-Val-Tyr-OMe in 2 ml of 95 % aqueous trifluoroacetic acid is stirred at room temperature for 2 hours. The mixture is concentrated by evaporation and the residue is `
purified by chromatography on 10 g of silica gel (eluant P). The frac-tions containing the product are concentrated by evaporation, and the residue is dissolved in DMF and precipitated with diisopropyl ether. The title compound is lyophilised from dioxane/tert.-butanol/water. FAB-MS:
(MtH) = 977; Rf(P) = 0.40; tRet(B) - 25.5 min.
: ~' .
The starting material is prepared in the following manner:
::
a) BBSP-Tyr(OtBu)-Cha-Val-Val-Tyr-OMe is prepared analogously to Example 7 from 20 mg of H-Tyr(OtBu)-Cha-Val-Val-Tyr-OMe, 22 mg of ~
2(S)-benzyl-3-tert.-butylsulfonylpropionic acid (BBSP-OH), 30 mg of HBTU -and 22 ~1 of triethylamine. The crude product is purified by flash chro-matography on 10 g of silica gel (eluant P) and lyophilised from dioxane/tert.-butanol/water. Rf(P) = 0.55.

b) H-Tyr(OtBu)-Cha-Val-Val-Tyr-OMe: A solution of 70 mg of Fmoc-Tyr-(OtBu)-ChaCVal-Val-Tyr-OMe in 2 ml of dimethylacetamide/piperidine 30:20 (v/v) is stirred at room temperature for 30 minutes. The mixture is concentrated by evaporation, and the residue is dissolved in DMF and precipitated with diisopropyl ether. The oily residue is washed with methylene chloride, dissolved in DMF and again precipitated with diiso-propyl ether at 0, and yields the title compound in the form of an amorphous solid. Rf(P) = 0.30; tRet(B) = 22-3 min-.;

; ' : ' . , ~ . . . . . . - . ". ., r. . . ~ , , , . , , . , , . . . . . . . . . , . " , . . . . .

_~ ZQ~37 c) Fmoc-Tyr(otBu)-chacval-val-Tyr-oMe is prepared analogously to Example 7 from 60 mg of H-ChaCVal-Val-Tyr-OMe, 55 mg of Fmoc-Tyr(OtBU)-OH, 46 mg of HBTU and 35 ~l of triethylamine. The crude product is purified by flash chromatography on 20 g of silica gel (eluant P). The fractions containing the product are concentrated by evaporation and the residue is precipitated from DMFldiisopropyl ether. Rf(P) = 0.60;
tR (B) = 32.4 min.

_ample 10: N-(2(R,S)-benzvl-3-pivaloyl-propionyl)-Ala-Cha-Val-Val-Tyr-OMe A mixture of 185 mg of crude H-Ala-Cha-Val-Val-Tyr-OMe, 17.5 mg of 2(R,S)-benzyl-3-pivaloylpropionic acid, 12.o mg of HOBH, 15.6 mg of DCCI
and 0.64 ml of DMF is stirred at room temperature for 16 hours. The reac-tion mixture is worked up analogously to Example 1, yielding, after chromatography (silica gel 60, eluant ethyl acetate) a diastereoisomeric mixture of the title compound. FAB-MS: (M+H) = 849.7; Rf(R) = 0.7;
tR t(B) = 27.5 and 27-9 min-The starting material is prepared in the following manner:

a) H-Ala-Cha-Val-Val-TY~r-OMe: A solution of 90 mg of BOC-Ala-Cha-Val-Val-Tyr-OMe in 2.3 ml of 95 % aqueous trifluoroacetic acid is stirred at 0 for 1.5 hours. A small amount of water is added to the reaction mixture in an ice bath and the trifluoroacetic acid is neutralised with solid NaHCO3. The residue is washed several times with ethyl acetate~ and the organic phases are combined and dried over sodium sulfate. The crude title compound is obtained after concentration by evaporation. Rf(R) = 0. ;

b) BOC-Ala-Cha-Val-Val-Tyr-OMe: A mixture of 109.5 mg of H-Cha-Val-Val-Tyr-OMe (Example 1 j)), 41.6 mg of BOC-Ala-OH, 49.6 mg of DCCI, 39.o mg of HOBH and 2 ml of DMF is stirred at room temperature for 5 hours. After cooling to 0 and filtration, the DMF is distilled off under a high ; -~
vacuum at a maximum o:E 60. The residue is dissolved in 5 ml of methylene chloride, and the organic phase is washed with 1 ml of aqueous sodium bicarbonate solution and dried over sodium sulfate. After concentration --' XC~C~5337 .. ~ ., . .

by evaporation, ~he crude title compound is purified by chromatography (38 g of silica gel 60, eluant ethyl acetate). FAB-MS: (M+H) = 719; -Rf(R) = 0.7.

Example 11: N-(2(R,S)-benzyl-3-pivaloyl-propionyl)-Ser-Cha-Val-Val-Tyr-OMe Analogously to Example 10, a diastereoisomeric mixture of the title com-pound is prepared from 80 mg of H-Ser~Cha-Val-Val-Tyr-OMe (crude pro-duct), 17.5 mg of 2(R,S)-benzyl-3-pivaloyl-propionic acid, 12.8 mg of HOBH and 15.8 mg of DCCI in 0.64 ml of DMF. FAB-MS: (M+H) = 865;
Rf(R) ~ 0.7; tRet(B) = 26-68 and 26-71 min-''-:.
The starting material is prepared in the following manner:

a) H-Ser-ChaCVal-Val-Tyr-OMe: Analogously to Example 10 a), the title compound is prepared from 95 mg of BOC-Ser-Cha-Val-Val-Tyr-OMe in 2.3 ml of 95 % trifluoroacctic acid. Rf(R) = 0.
' : ' b) BOC-Ser-ChaCVal-Val-Tyr-OMe: Analogously to Example 10 b), the title compound is prepared from 109.5 mg of H-ChaCVal-Val-Tyr-OMe, 45.1 mg of BOC-Ser-OH, 39.8 mg of HOBH and 49.6 mg of DCCI and is purified by chro-matography. FAB-MS: (M~H) a 735; Rf(R) = 0.65.

Example 12: N-(2(R,S)-benzyl-3-pivaloyl-propionyl)-Phe-ChaCVal-Val-Tyr-OMe 43.5 mg of H-Phe-Cha-Val-Val-Tyr-OMe and 20.8 mg of 2(R,S)-benzyl-3-pivaloyl-propionic acid are dissolved in 2 ml of DMF, and 31.7 g of BOP
and 14.6 ~l of triethylamine are added thereto. The solution is stirred at room temperature for 15 hours and then concentrated by evaporation.
The residue is digested in a small amount of diisopropyl ether. FABi-MS:
(M+H) = 925; Rf(S) = 0.5; tR t(B) = 30-7 and 31.1 min.

The starting material is prepared in the following manner:

:: ~

;2~ 3~7 a) H-Phe-ChaCVal-Val-Tyr-oMe: A solution of 83 mg of Ymoc-Phe-ChaCVal-Val-Tyr-OMe, 2.4 ml of piperidine and 2.4 ml of DMF is stirred at room temperature for 90 minutes and then concentrated by evaporation. The residue is dissolved in a small amount of methylene chloride and pre-cipitated with diisopropyl Pther. The prec:ipitate is filtered off at 0 and then lyophilised from dioxane/water 9::l. FAB-MS: (M+H) = 695;
Rf(Q) = 0.36.

b) Fmoc-Phe-ChaCVal-Val-Tyr-OMe: A mixture of 50 mg of H-Cha-Val- --Val-Tyr-OMe, 67.3 mg of Fmoc-Phe-OTcp, 17 ~1 of N-ethyldiisopropylamine and 1.2 ml of DMF is stirred at room temperature for 75 minutes. The reaction mixture is concentrated by evaporation, and the residue is pre-cipitated with 5 ml of diisopropyl ether. The precipitate is filtered off and precipitated a second time from DMFldiisopropyl ether. Rf(Q) = 0.37.
xample 13: N-(2(R,S)-benzyl-3-pivaloyl-propionyl)-Leu-Cha-Val-Val-Tyr-OMe 35.5 mg of H-Leu-ChaCVal-Val-Tyr-OMe and 16 mg of 2(R,S)-benzyl-3-pivaloyl-propionic acid are dissolved in 2 ml of DMF, and 28.5 mg of BOP
and 11.2 ~1 of triethylamine are added thereto. After stirring at room temperature for 150 minutes, the reaction mixture is concentrated, and the rasidue is digested in 20 ml of diisopropyl ether. FAB-MS:
(M+H) = 891; Rf(Q) = 0-57; tR t(B3 = 30-1 and 30-4 min~
'~`' ,~ -,:' The starting material is prepared in the following manner: ~
, : ' . ': ': "
a) H-Leu-Cha-Val-Val-Tyr-OMe: A solution of 108 mg of Fmoc-Leu-Cha-Val-Val-Tyr-OMe, 3.2 ml of piperidine and 3.2 ml of DMF is stirred at room temperature for 60 minutes and then concentrated by evaporation. The residue is dissolved in a small amount of DMF and precipitated with 20 ml of diisopropyl ether. The precipitate is filtered off at 0 and then lyophilised from dioxane/water 9:1. FAB-MS: (M+H) = 661; Rf(Q) = 0.64.

b) Fmoc-Leu-Cha-Val-Val-Tyr-OMe: A mixture of 80 mg of H-Cha-Val-Val-Tyr-OMe, }01 mg of Fmoc-Leu-OTcp, 27.5 ~1 of N-ethyldiisopropylamine and 1.4 ml of DMF is stirred at room temperature for 90 minutes. The reaction - ~

~:' ':'',~,' ., ,"'~ ,.

20~5~

mixture is concentrated by evaporation, and the residue is precipitated with 100 ml of diisopropyl ether. The precipitate is filtered off and then lyophilised from dioxane/water 9:1. Rf(Q) = 0.375.

Example 14: BBSP-Leu-Cha~Val-Val-Tyr-OMe 35.5 mg of H-Leu-Cha-Val-Val-Tyr-OMe and 1~.4 mg of 2(S)-benzyl-3-tert.-butylsulfonylpropionic acid (BBSP-OH) are dissolved in 1 ml of DMF, and 28.5 mg of BOP and 11.2 ~1 of triethylamine are added thereto. After stirring at room temperature for 5 hours, the reaction mixture is con-centrated, and the residue is digested in diisopropyl ether. FAB-MS:
(M+H) = 927.5; Rf(Q) = 0.54; t (B) = 28 0 Example 15: BBSP-Leu-ChaCVal-Val-p-biphenylylmethylamide 40 mg of H-Leu-Cha-Val-Val-~-biphenylylmethylamide and 18.4 mg of BBSP-OH are dissolved in 1 ml of DMF, and 28.5 mg of BOP and 11 ~1 of triethylamine are added thereto. After stirring at room temperature Eor 5 hours, the reaction mixture is concentrated, and the residue is digested in diisopropyl ether. FAB-MS: (M~H) = 916; Rf(Q) = 0.58.
.,, The starting material is prepared in the following manner:

a) H-Leu-ChaCVal-Val-p-biphenylylmethylamide: A solution of 108 mg of ~
Fmoc-Leu-ChaCVal-Val-~-biphenylylmethylamide, 3 ml of piperidine and -3 ml of DMF is stirred at room temperature for 60 minutes and then con-centrated by evaporation. The residue is dissolved in a small amount of DMF and precipitated with 20 ml of diisopropyl ether. The precipitate is filtered off at 0 and then lyophilised from dioxanetwater 9:1. FAB-MS:
(M+H) = 649; Rf(Q) = 0.72.

b) Fmoc-Leu-Cha~Val-Val-p-biphenylylmethylamide: A mixture of 100 mg of h-Cha-Val-Val-~-biphenylylmethylamide, 120 mg of Fmoc-Leu-OTcp, 35 ~1 of N-ethyldiisopropylamine and 2 ml of DMF is stirred at room temperature for 90 minutes. The reaction mixture is concentrated by evaporation, and the residue is precipitated with 100 ml of diisopropyl ether. The pre-cipitate is filtered off and then lyophilised from dioxane/water 9:1.
Rf(Q) = 0.41.

-" 2~Q~;~37 c) H-ChacVal-Val-p-biphenylylmethylamide: 290 mg of N-(5(S)-azido-6-cyclohexyl-4(S)-hydroxy-2(s)-i50propylhexanoyl)-val-~-biphenylylmeth amide are dissolved in 40 ml of methanol, 70 mg of palladium-on-carbon (5 % Pd) are added thereto and reduction is carried out with hydrogen.
After 2 hours at room temperature, the catalyst is filtered off, the solution is concentrated and the residue is precipitated. FAB-MS:
(M+H) = 536; Rf(T~ = 0.23.

d) N-(5(S)-azido-6-cyclohexyl-4(S)-hYdroxy-2(S)-isopropYlhexanoyl)-Val- ~ ~;
p-biphenylylmethylamide: 360 mg of tetrabutylammonium fluoride are added to 386 mg of N-(5(S)-azido-6-cyclohexyl-4(S)-tert.-butyldimethylsilyloxy-2(S)-isopropyl-hexanoyl)-Val-~-biphenylylmethylamide in 5 ml of DMF.
After 4 hours, the solution is concentrated and the residue is taken up `
in approximately 100 ml of ethyl acetate and washed with sodium bicar- ;~
bonate solution. After concentration of the solution, the residue is crystallised from methylene chloride/hexane. FAB-MS: (M+H) = 562;
Rf(U) = 0.12. ;;

e) N-(5(S)-azido-6-cyclohexyl-4(S)-tert.-butyldimethylsilyloxy-2(S)-iso- ;;
propyl-hexanoyl?-Val-p-biphenylylmethylamide: 376 mg of 5(S)-azido-6-cyclohexyl-4(S)-tert.-butyldimethylsilyloxy-2(S)-isopropyl-hexanoic acid (J. Org. Chem. 54, 1178 (1989)) and 250 mg of valine-~-biphenylylmethyl- ;
amide are dissolved in 10 ml of DMF, and 404 mg of BOP and 0.16 ml of triethylamine are added thereto. After 16 hours at room temperature, the ; ; `~
reaction m~xture is concentrated, and the residue is digested with diiso-propyl ether. FAB-MS: (M+H) = 676; Rf(~) = 0.45.

f) Valine-p-biphenylylmethylamide: 980 mg of BOC-Val-~-biphenylylmethyl-amide are left to stand for 30 minutes at room temperature in 10 ml of dioxane/4N HCl. The reaction mixture is then concentrated and partitioned between ethyl acetate and lN NaOH. The organic phase is concentrated and the residue is chromatographed on silica gel. Rf(F) = 0.4.

r~
20~ii337 g) BOC-Val-p-biphenylylmethylamide: 3.9 g of N-tert.-butoxycarbonyl-L-valine-N'-hydroxysuccinimide ester and 2.7 g of biphenylylmethylamine are stirred in 150 ml of methylene chloride for 1 hour at room temperature.
The mixture is filtered through silica gel and concentrated by evapora-tion, and the residue is crystallised from hexane. FAB-MS: (M-~H) = 383;
Rf(U) = 0.28.

Example 16: BBSP-Leu-Cha-Val-5-phenylpentylamide 65 mg of H-Leu-ChaCVal-5-phenylpentylamide and 31 mg of BBSP-OH are dissolved in 1.5 ml of DMF, and 44 mg of BOP and 18 ~1 of triethylamine are added thereto. After stirring for 5 ~ hours at room temperature, the solvent is removed and the residue is digested with diisopropyl ether.
FAB-MS: (M+H) = 797; Rf(Q) = 0.45.
' The starting material is prepared in the following manner:

a) H-Leu-Cha-Val-5-phenylpentylamide: A solution of 150 mg of Fmoc-Leu-ChaCVal-5-phenylpentylamide, 4 ml of piperidine and 4 ml of DMF is stirred for 60 minutes at room temperature and then concentrated by evaporation. The residue is dissolved in a small amount of DMF and pre-cipitated with 20 ml of diisopropyl ether. The precipitate is filtered off at 0 and then lyophilised from dioxane/water 9:1. FAB-MS:
~ H) = 530; Rf(Q) = 0.61.

b) Fmoc-Leu-Cha-Val-5-phenylpentylamide: A mixture of 100 mg of H-Cha-Val-5-phenylpentylamide, 100 mg of Fmoc-Leu-OTcp, 35 ~1 of N-ethyldiisopropylamine and 2 ml of DMF are stirred for 90 minutes at room temperature. The reaction mixture is concentrated by evaporation and the residue is precipitated with 100 ml of diisopropyl ether. The pre-cipitate is filtered off and then lyophilised from dioxane/water 9:1.
FAB-MS: (M+H) = 739; Rf(Q) = 0.39.

c) H-ChaCVal-5-phenylpentylamide: 240 mg of 5(S)-azido-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropyl-hexanoic acid 5-phenylpentylamide are dissolved in 40 ml of methanol; 70 mg of palladium-on-carbon (5 % Pd) are -' ;20~37 added and the whole is reduced with hydrogen. After 2 hours at room tem- -~
perature, the catalyst is filtered off, the solution is concentrated and the residue is precipitated. FAB-MS: (M+H) = 417; Rf(T) = 0.19.

d) 5(S)-azido-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropyl-hexanoic acid 5-phenylpentylamide: 279 mg of 5(S)-azido-6-cyclohexyl-2(S)-isopropyl-4(S)-hexanolide (J. Org. Chem. 54, 1178 (1989)) are heated for 3 hours at `60 in 816 mg of 5-phenylpentylamine. The mixture is then chromatographed on silica gel. FAB-MS: (M~H) = 443; Rf(V) = 0.4. ~;~

Example 17: BBSP-Val-Leu-Val-Val-Tyr-OMe The title compound is prepared analogously to Example 7 from 30 mg of ;~
HCl-H-Val-Leu-Val-Val-Tyr-OMe, 40 mg of 2(S)-benzyl-3-tert.-butylsul- ;~
fonylpropionic acid (BBSP-OH), 53 mg HBTU and 40 ~l of triethylamine, ;
purified by flash chromatography on silica gel (eluant P) and lyophilised from dioxane/tert.-butanol/water. ~ -''` :'~' The starting material is prepared in the following manner~

a) HCl-H-Val-LeuCVal-Val-Tyr-OP(e i9 prepared analogously to Exampla ~;
1 l) from 55 mg of BOC-Val-LeuCVal-Val-Tyr-OMe and 5 ml of 4N HCl in dioxane. The product is lyophilised from dioxane. -b) BOC-Val-Leu-Val-Val-Tyr-OMe is prepared analogously to Example 7 b) from 60 mg of H-Leu-Val-Val-Tyr-OMe, 77 mg of BOC-Val-OH, 135 mg of HBTU and 100 ~l of triethylamine.

c) H-LeuCVal-Val-Tyr-OMe is obtained analogously to Example 1 j) from 90 mg of Z-LeuCxVal-Val-Tyr-OMe by catalytic hydrogenation in 10 ml of methanol/water 9:1 and 15 mg of palladium-on-carbon (10 % Pd). --d) Z-Leu - Val-Val-Tyr-OMe: Analogously to Example 1 i), 150 mg of Z-Leu - Val-OH (preparation in accordance with EP 143 746) are reacted -~
with 115 mg of H-Val-Tyr-OMe, 85 mg of DCCI, 62 mg of HOBt and 45 ~l of N-methylmorpholine. The title compound is obtained after flash chromato-graphy (eluant P).
'~
:' . ~ ' . . .

` ;20~5~7 Example 18: BBSP-Val-Sta-Val-Tyr-OH
On 260 mg (0.11 mmol) of Fmoc-Tyr(OtBu)-p-benzyloxybenzyl ester-poly-styrene resin (1 % cross-linked) (Novabiochem, Laufelfingen, Switzerland), on a frit, the process described in the following is applied repeatedly for the alternating removal of the Fmoc protecting group and for coupling the acid derivatives. The washing operations with in each case approximately 3 ml of solvent and the reaction operations are carried out with shaking.

In the first stage, Fmoc-Val-OH is coupled as follows:

.
Step No. RepetitionDuration Operation --1 7 times 2 min. Removal of the Fmoc protecting group with piperidine/D~ 80:20 (v/v) 2 twice1 min. Washing with DMA
3 once30 min. Preactivation for coupling: 3 eq.
Fmoc-Val-OH, 3.3 eq. 0.5M HOBt in D~IA, 3.3 eq. 2.0M diisopropyl-carbodiimide in DMA
4 once1 hour Coupling at room temperature after addition of the previously prepared coupling mixture to the resin twice1 min. Washing with DMA
6 once5 min. Acetylation of the unreacted amino groups with acetic anhydride/pyridine/DMA 10:10:80 (v/v) 7 3 times 1 min. Washing with DMA

8 twice ~ 1 min. Washing with isopropanol 9 twice1 min. Washing with DMA -~

Analogously to the above, in the second stage Fmoc-Sta-OH is coupled in steps 3 and 4 with a reaction time of 4 hours; steps 5 and 6 are omitted.
The coupling of Fmoc-Val-OH in the third stage and of 2(S)-benzyl-3-. . " ' . ' :, , :

'`"''. '. .' .'"''.' .,, ' "' ' .' '' , '~.' ,'- :" , ' ""' '" ,' ~ ', ' : '. ' ' ' : ' ': ' ', ' " . . ,. ' " ' ' ' ', , . . . ,. . ' ' :

Z0~ 3~

tert.-butylsulfonylpropionic acid (BBSP-OH) in the fourth stage in turn ;
takes place with a reaction time of 1 hour in steps 3 and 4 and without steps 5 and 6.

The completed peptide synthesis resin so obtained is shaken at room tem-perature twice for 5 minutes each time with 3 ml of trifluoroacetic acid/water/1,2-ethanedithiol 95:5:2 (v/v) each time, filtered off and then washed twice with 3 ml of 1,2-dichloroethane each time and twice with 3 ml of trifluoroethanol each time. The filtrates are concentrated by evaporation in vacuo. In order to remove all of the protecting groups, ;~
the residue is dissolved in 2 ml of 95 % aqueous trifluoroacetic acid and, after 1 hour, concentrated by evaporation 1n vacuo. The residue is again dissolved in 2 ml of 95 % trifluoroacetic acid, and the peptide is ~ ;~
precipitated by the dropwise addition of diisopropyl ether. The precipi-tate is dissolved in 1,2-dichloroethane and precipitated again by the ~`
addition of diisopropyl ether. The title compound is obtained by lyophilisation from dioxane/tert.-butanol/water. FAB-MS: (M+H) = ôO3;
Rf(O) = 0-43~ tRet(B) = 22-0 min-Example 19: BBSP-Val-Sta-Val-TYr-OMe A solution of 3 mg oE BBSP-Val-Sta-Val-Tyr-OH in 3 ml of lN HCl in methanol is left for l hour at room temperature and then concentrated by evaporation. Lyophilisation of the residue from dioxane yields the title -compound. FAB-MS: (M+H) = 817; Rf(O) = 0.75; tR t(B) = 24.1 min.

Example 20: BBSP-Val-ACHPA-Val-Tyr~OH
, Analogously to Example 18, the following acid derivatives are coupled to 240 mg ~0.095 mmol) of Fmoc-Tyr(OtBu)-p-benzyloxybenzyl ester-polystyrene resin (1 % cross-lin~ed):
!
1. Fmoc-Val-OH
2. Fmoc-ACHPA-OH, 4 hours' reaction time, without steps _, 6 3. Fmoc-Val-OH, without steps , 6 4. BBSP-OH, without steps _, 6.
' .
`' :: ' .:', , ` 2C~337 -- :

The peptide is released from the resin as in Example 18 and precipitated twice from DMF by the dropwise addition of diisopropyl ether at 0.
Lyophilisation from dioxane/tert.-butanol/water yields the title com-pound. FAB-MS: (M+H) = 843; Rf(O) = 0.40; tR t(B) = 27.6 min.

The starting material is prepared in the following manner:

a) Fmoc-ACHPA-OH- A solution of 660 mg of BOC-ACHPA-OH (J. Med. Chem. 28, 1779 (1985)) in 25 ml of 4N HCl in dioxane is stirred for 30 minutes at room temperature. After dilution with 10 ml of dioxane and lyophilisa-tion, HCl-H-ACHPA-OH is obtained. 247 mg of sodium bicarbonate and 545 mg of Fmoc-N-hydroxysuccinimide are added to a solution of 390 mg of this compound in 10 ml of dioxane/THF/water 1:1:1 (v/v). The turbid mixture is stirred overnight at room temperature, acidified to pH 2 with 2N HCl and concentrated to 5 ml. The concentrate is partitioned between O.lN HCl and methylene chloride, and the organic phases are filtered through cotton wool and concentrated by evaporation. The oily residue is purified by flash chromatography on 50 g of silica gel (eluant P) and the product-containing fractions are concentrated by ~vaporation. Crystalllsation of the resulting oil from ethyl acetate/hexane yields the title compound.
M.p. = 144; Rf(P) ~ 0.33; tRet(B) = 27-9 min-Example 21: BBSP-Phe-Sta-Val-Tyr-OH
Analogously to Example 18, the following acid derivatives are coupled to 300 mg (0.11 mmol) of Fmoc-Tyr(OtBu)-~-benzyloxybenzyl ester-polystyrene resin (1 % cross-linked):

1. Fmoc-Val-OH
2. Fmoc-Sta-OH, 4 hours' reaction time, without steps 5, 6 -3. Fmoc-Phe-OH, without steps 5, 6 4. BBSP-OH, without steps 5, 6.

The peptide is released from the resin as described in Example 18 and precipitated from DMF by the dropwise addition of diisopropyl ether. The precipitate is separated by preparative HPLC (C1g Nucleosil~ 5 ~, 25 x 2 cm, water/acetonitrile 60:40 with 0.1 % trifluoroacetic acid in ~ 2~337 .
.

each case, 600 bar) and the product-containing fractions are concentrated to half the volume in vacuo. After lyophilisation of the residual volume, the title compound is obtained. FAB-MS: (M+H) = 851; Rf(P) = 0.24;
tRet(B) = 23.9 min.
.
Lxample 22: BBSP-Val-Phe - Pro-Val-Tyr-OH
Analogously to Example 18, the following acid derivatives are coupled to 240 mg (0.095 mmol) of Fmoc-Tyr(OtBu)-~-benzyloxybenzyl ester-polystyrene resin (1 % cross-linked): ~ ~`
` ~:
1. Fmoc-Val-OH
2. Fmoc-PheredPro-OH, 4 hours' reaction time, without steps 5, 6 3. Fmoc-Val-OH, without steps 5, 6 4. BBSP-OH, without steps 5, 6.
: ~ .
The peptide is released from the resin as in Example 18 and precipitated twice with diisopropyl ether/petroleum ether 1:1. Lyophilisation from tert.-butanol/glacial acetic acid 9:1 yields the title compound; FAB-MS:
(M+H) = 885; tRet(C~ = 18.9 min.

The starting material is preparcd in the following manner~

a) N-BOC-L-phenylalaninol: 18.2 g of L-phenylalaninol and 28.4 g of -di-tert.-butyl dicarbonate are reacted for 2 hours at room temperature in 500 ml of CHzCl2. The CH2Cl2 is then distilled off under a water-jet vacuum and the crystalline title compound ls recrystallised from ether.
M p. 93-94. ` ~

b) N-BOC-L-phenylalaninal: A solution of 9.12 ml of DMSO in 100 ml of -CH2Cl2 is added dropwise at -60 to a solution of 5.64 ml of oxalyl chloride in 100 ml of CHzC12. When the addition is complete, the mixture ` `
is left to react for a further 15 minutes to complete the reaction and ~ -then a solution of 15.06 g of N-BOC-L-phenylalaninol in 200 ml of CHzClz is added. After 1 hour at -60, the reaction mixture is poured onto ice and the aqueous phase is adjusted to pH 3 with lN HCl. The organic phase is washed once with ice-cold aqueous NaHCO3 solution and once with water, ' ~

' :. `':
. . .
` ' ,:,`:.' ~` Z~(35337 .

dried over MgSO4 and concentrated by evaporation in vacuo at room temperature. The title compound, which remains, is recrystallised from hexane and stored in a deep-free~e because of the risk of racemisation.
M.p. 74-76; [~]D = -38.1 (c = 1.09, CH30H).

c) BOC-Phe - Pro-OMe: 12.0 g of N-BOC-L-phenylalaninal and 45.5 g of L-proline methyl ester hydrochloride are dissolved in 400 ml of methanol and reacted with 2.36 g of sodium cyanoborohydride (85 %) at room temperature. After stirring for 6 hours at room temperature, the solvent is distilled off under a water-jet vacuum and the crude title compound is purified by flash chromatography on 600 g of silica gel 60 (eluant A). Yellow, viscous oil, Rf(A) = 0.65. According to lH-NMR
(CDCl3), an approximately 9:1 mixture of diastereoisomers is obtained, resulting from the fact that the N-BOC-L-phenylalaninal used is not 100 %
enantiomer-pure.

d) BOC-PheredPro-OH: 6.18 g of BOC-PheredPro-OMe are dissolved in 70 ml of methanol/water 4:1 and hydrolysed overnight at room tempera-ture with lô.7 ml of lN NaOH. The methanol is then distilled off in vacuo and the pH is adjusted to 9 with approximately 15 ml of lN ~Cl while cooling with ice. After drying over sodium sulfate, ethyl acetate extraction yields the crude crystalline title compound. After digesting in a small amount of cold ethyl acetate, the pure title compound can be `
obtained. M.p. 160-166; Rf(V) = 0.35.

e) H-Phe - Pro-OH-2HCl: 696.8 mg of BOC-Phe - Pro-OH are stirred for 30 minutes at room temperature in 28 ml of 4.25N hydrochloric acid in dioxane. The whole is then concentrated by evaporation in vacuo and the title compound is isolatsd in the form of a white powder and further processed directly.

f) Fmoc-Phe - Pro-OH: 0.166 ml of triethylamine is added to 186 mg of H-Phe - Pro-OH-2HCl (crude product) and 133.5 mg of Fmoc-N-hydroxysuccinimide ester in 4 ml of water and the whole is stirred for 4 hours at room temperature. Ethyl acetate is added to the reaction mixture and the aqueous phase is adjusted to pH 4-6 with lN aqueous HCl.

~ 5~3~

The organic phase is separated off and dried over sodium sulfate and the crude title compound is obtained by concentration by evaporation under a ~`
water-jet vacuum. The pure compound is obtained by chromatography on 7 g of silica ~el 60 (eluant ethyl acetate:methanol = 4:1). Rf(V) = 0.4;
FAB-MS: (M+H) = 471; [~]D = -27.1 (c = 0.634, CHCl3).

Example 23: BBSP-Val-Phe - Pro-Val-Tyr-OMe The title compound is prepared analogously to Example 1 from 65 mg of H-Val-Pher ~ro-Val-Tyr-OMe (crude product), 32.4 mg of 2(S)-benzyl-3-tert.-butylsulfonylpropionic acid (BBSP-OH), 17.5 mg of HOBt, 25.8 mg of DCCI and 21 mg of N-methylmorpholine in 16 ml of DMF. Rf(R) = 0.55;
FAB-MS: (M+H) = 890: tRet(B) = 23-4 min-The starting material is prepared in the following manner:

a) H-Val-Phe - Pro-Val-Tyr-OMe: 180 mg of BOC-Val-Phe - Pro-Val-Tyr-OMe are treated at 0 for 90 minutes with 5 ml of 95 % aqueous tri-fluoroacetic acid. The whole is then workecl up with CH2Cl2 and solid NaHCO3. The organic phase is filtered over Hyflo~ and then washed with a `
small amount of water. After drying over MgSO4 and evaporating the solvent, the title compound is obtained. FAB-MS: (M+H) = 624. ;~

b) BOC-Val-PheredPro-Val-TYr-OMe is prepared analogously to Example 1 from 39 mg of H-Phe - Pro-Val-Tyr-OMe, 17.9 mg of BOC-Val-OH,~ ;
14.7 mg of HOBH and 18.4 mg of DCCI and purified by chromatography on silica gel 60 (eluant R). Rf(R) = 0.5; FAB-MS: (M+H) = 724. `

c) H-Phe - Pro-Val-Tyr-OMe is prepared analogously to Example 23 a) from 300 mg of BOC-PheredPro-Val-Tyr-OMe and 6 ml of 95 % aqueous trifluoroacetic acid and isolated by precipitation from ether/hexane.
FAB-MS: (M+H) = 525. ~ -d) BOC-Phe - Pro-Val-Tyr-OMe is prepared overnight at room tempera-ture from 348 mg of BOC-Phe - Pro-OH, 294.3 mg of H-Val-Tyr-OMe (Example 1 h)), 183.6 mg of HOBt and 247.6 mg of DCCI in 40 ml of DMF.
For working up, most of the DMF is distilled off under a high vacuum at -. z0~533'~

60, 0.5 ml of acetic acid/H2O 1:1 is ad~ed to the residue at 0 and the whole is stirred for 30 min. The yellow suspension is filtered over Hyflo~ and then washed with a small amount of DMF and the filtrate is concentrated under a high vacuum. The concentrate is taken up in 100 ml of CH2Cl2, 10 ml of water are added and the aqueous phase is adjusted to pH 9 with 1N NaOH. After separating the organic phase and washing it once with a small amount of water, it is dried over sodium sulfate and the crude title compound is isolated therefrom by concentration by evapora-tion. Column chromatography on silica gel 60 (eluant W) yields the pure title compound which can be recrystallised from toluene/hexane. M.p.
173-175; FAB-MS: (M+H) = 625; Rf(~) = 0.3.

Example 24: BBSP-Val-CharedPro-Val-Tvr-OMe The title compound is prepared analogously to Exàmple 1 from 172 mg of -H-Val-Cha - Pro-Val-Tyr-OMe (crude product), 85.4 mg of BBSP-OH, 46 mg of HOBt, 67.6 mg of DCCI and 55.2 mg of N-methylmorpholine in 15 ml of DMF. Rf(R) = 0.5; FAB-MS: (M~H) = 896; tRet(B) = 24-7 min-The starting material is obtained in the following manner:

a) H-Val-Cha dPro-Val-Tyr-OMe: 280 mg of BOC-Val-Cha - Pro-Val-Tyr-OMe are treated analogously to Example 23 a) with 5 ml of 95 %
aqueous trifluoroacetic acid and further processed in the form of the crude product.

b) BOC-Val-CharedPro-Val-Tyr-OMe: The title compound is prepared analogously to Example 1 from 1.06 g of H-Cha - Pro-Val-Tyr-OMe (crude product), 476 mg of BOC-Val-OH, 395 mg of HOBH and 496 ng of DCCI
in 25 ml of DMF and purified by chromatography on silica gel 60 (eluant ethyl acetate). Rf(R) = 0.65; IR(CH2Cl2): 2920, 1735, 1665 cm c) H-Char dPro-Val-Tyr-OMe: 1.129 g of BOC-CharedPro-Val-Tyr-OMe are treated analogously to Example 23 a) with 20 ml of 95 % aqueous trifluoroacetic acid and further processed in the form of the crude product.

,.. .. .. . .

2~ 3~7 d) Boc-charedpro-val-Tyr-oMe: The title co~pound is prepared analogously to Example 1 from 769 mg of BOC-Cha - Pro-OH, 639 mg of H-Val-Tyr-OMe, 398 mg of HOBt and 537 mg of DCCI in 100 ml of DMF and purified by chromatography on silica gel 6Q (eluant methanol).
Rf(MeOH) = 0.88; IR(CHzCl2): 2920, 1740, 1675 cm .
e) BOC-Cha - Pro-OH: 2.09 g of BOC-Phe - Pro-OH are hydrogenated under normal pressure in 40 ml of THF with 2.27 ml of methanolic HCl and 0.4 g of Nishimura catalyst. The whole is then filtered over Hyflo~, the filter residue is washed with a small amount of ;
methanol/THF, and ethyl acetate and aqueous sodium bicarbonate solution are added to the filtrate. The pH of the aqueous phase is adjusted to 9 and the organic phase is separated off, dried over sodium sulfate and ;~
concentrated ln vacuo. Recrystallisation of the residue from ethyl ~
acetate/hexane yields the pure title compound. M.p. 155-158; FAB-MS: --;
(M~H) = 355; [~]D = -25 (c = 1.07, CHCl3). ~ `

Example 25: BBSP-Val-Cha- -Val-Val-Tyr-OH
Analogously to Example 18, the following acid derivatives are coupled to 260 mg (0.11 mmol) of Fmoc-Tyr(OtBu)-~-benzyloxybenzyl ester-polystyrene resin (1 % cross-linked):

1. Fmoc-Val-OH
2. Fmoc-CharedVal-OH, 4 hours' reaction time, without steps 5, 6 3. Fmoc-Val-OH, without steps 5, 6 4. BBSP-OH, without steps 5, 6. ~;

The peptide is released from the resin as in Example 18 and precipitated twice with diisopropyl ether/petroleum ether 1:1. Lyophilisation from tert.-butanol yields the title compound: FAB-~IS: (M+H) = 877; -~
tRet(C) = 17.75 min.

The starting material is prepared in the following manner: ;~

. ~, ... . .. .. . . .

, , ,, , ,.. ,. . , .. , ., , , , . " , . . , . , , . .. . . ~ . . .

3~

a) Fmoc-Cha - Val-OH is prepared analogously to Example 22 f) from 1.71 g of H-CharedVal-OH-2HCl (crude product) and 1.94 g of Fmoc-N-hydroxysuccinimide ester in 100 ml of water and 2.3 ml of triethylamine.
M.p. (methanol) 188 (decomposition); FAB-MS: (M+H) = 479.

b) H-CharedVal-OH-2HCl is prepared analogously to Example 22 e) from 1.85 g of BOC-CharedVal-OH in i5 ml of 4.25N hydrochloric acid in dioxane and used further in the crude state.

c) BOC-Cha - Val-OH is prepared analogously to Example 24 e) from 540 mg of BOC-PheredVal-OH, 0.5 g oE Nishimura catalyst and 3.78 ml of methanolic HCl in 70 ml of methanol. M.p. 187 (decomposition);
FAB-MS: (M+H) = 357; IR(KB ): 3380, 2910, 1690 cm d) BOC-PheredVal-OH is prepared analogously to Example 22 d) from 730 mg of BOC-Phe Val-OMe and 2,2 ml of lN NaOH in 8 ml of methanol/water 4:1. M.p. 207 (decomposition); FAB-MS: (M+H) = 351;
IR(KBr): 3365, 2970, 1690 cm e) BOC-PheredVal-OMe is prepared analogously to Example 22 c) from 3.7 g of N-BOC-L-phenylalaninal, 14.8 g of L-valine methyl ester hydro-chloride and 770 mg of sodium cyanoborohydride (85 %) in lS0 ml of methanol. M.p. 74-76 (ether/pentane); [~]D0 = -17.5 (c = 0.85, CHCl3).

Example 26: Gelatin solution A sterile-filtered aqueous solution of Z-Arg-Arg-Pro-Phe-Val-ChaCVal-Val-Tyr-OMe is mixed with a sterile gelatin solution containing phenol as preservative, while heating under aseptic conditions, in such amounts that 1.0 ml of solution has the following composition:
~ .:
Z-Arg-Arg-Pro--Phe-Val-Cha-Val-Val-Tyr-OMe 3 mg ~ -gelatin 150.0 mg phenol 4.7 mg distilled water up to 1.0 ml The mixture is introduced into 1.0 ml phials under aseptic conditions. ~;

':.': '~' ~ ' ' : ~ :

zc~ 3~

Example 27: Sterile drv substance for injection 5 mg of Z-Arg-Arg-Pro-Phe-Val-chaCval-val-Tyr-OMe are dissolved in 1 ml of an aqueous solution with 20 mg of mannitol. The solution is sterile-filtered and introduced under aseptic conditions into a 2 ml ampoule, deep-frozen and lyophilised. Before use, the lyophilised substance is dissolved in l ml of distilled water or 1 ml of physiological saline solution. The solution is administered intramuscularly or intravenously.
This formulation may also be introduced into double-chamber syringe ampoules.

Example 28: Nasal spray -500 mg of finely ground (<5.0 ~m) BBSP-Val-Cha-Val-Val-Tyr-OMe 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. The spray container contains approximately 100 single doses which may be administered singly.

Example 29: Lacquer-coated tablets The following constituents are processed for the preparation of 10,000 tablets each containing 100 mg of active ingredient:

BBSP-Val-ChaCVal-Val-Tyr-OMe 1000 g corn starch 680 g colloidal silica 200 g magnesium stearate 20 g -stearic acid 50 g sodium carboxymethyl starch 250 g water q.s.

A mixture of BBSP-Val-ChaCVal-Val-Tyr-OMe, 50 g of corn starch and the ~ -colloidal silica is processed with a starch paste consisting of 250 g of corn starch and 2.2 kg of demineralised water to form a moist mass. This mass is forced through a sieve of 3 mm mesh size and dried for 30 minutes 3~

at 45 in a fluidised-bed drier. The dry granulate is 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 compressed to form slightly convex tablets.

The compacts are coated in a coating vesse:L of 45 cm diameter by uniform spraying for 30 minutes with a solution of 20 g of shellac and 40 g of hydroxypropylmethylcellulose (low viscosity) in 110 g of methanol and 1350 g of methylene chloride; drying is effected by blowing in air simultaneously at 60.

Instead of the active ingredients mentioned in Examples 26 to 29, it isalso possible to use in these Examples the same àmount of a different active ingredient from the preceding Examples.

Example 30: Inhibition of isolated HIV-l ~ag protease 10 111 of a solution of }IIV-1 gag protease (acetone extract of a gag protease expressed in E. coli according to J. Hansen et al., Tlle EMBO
Journal 7, 1735 (1988)) and 190 ,ul of 13-morpholinoethanesulfonic acid-buffer solution pH 6 containing 0.01 % 2-amino-4-nitrophenol as the internal standard are pre-incubated at 37. 10 111 of a 0.24 mM DMSO solu--tion of the substrate H-Arg-Arg-Ser-Asn-Gln-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Asn-Ile-Gln-Gly-Arg-Arg-OH (icosapeptide according to J.
Schneider et al., Cell 54, 363 (1988), prepared in an automated peptide synthesising apparatus with Fmoc-protected amino acisl units) and 10 lll of a DMSO solution of the compound to be investigated for its inhibiting action, in a concentration of 22 x 10 M or 22 x 10 M, are then added simultaneously. After one hour, 50 111 of reaction solution are removed, 5 ~11 of 0.3M perchloric acid are added thereto and the whole is centrifuged. The amount of unconsumed substrate and the cleavage products in the supernatant solution are determined by HPLC and the percentage -inhibition at 10 M and 10 M is calculated therefrom.

`"'~ ~' ~ - :
2~1~S337 For the HPLC analysis there is used a 125 x 4.6 mm reversed phase C18 Nucleosil~ 5 ~ column; gradient 10 % acetonitrile/0.1 % trifluoroacetic acid in water - ~ 25 % acetonitrilelO.08 % trifluoroacetic acid in water in 30 min., flow rate 1.5 ml/min.

The compounds of the majority of the preceding Examples have, at con-centrations of 10 M, an inhibiting action of more than 80 % and, at 10 6M, an inhibiting action of more than 50 %.

Example 31_ Protection against HIV infection in a cell test The cell line MT-2 which is used is a human T-cell leukaemia that has been transformed with HTLV-1 and continuously produces HTLV-1, which renders the cells extremely sensitive to the cytopathogenic effect of HIV
(Science 229, 563 (1985)). The MT-2 cells are cultivated in RPMI 1640 medium containing 12 % heat-deactivated foetal calf serum (Seromed Biochrom KG, Berlin, Federal Republic of Germany), glutamine and standard antibiotics. The cells are kept at 37 in a humidified atmosphere of 5 %
CO2 in air and are used for the cell test in the logarithmic growth phase.

HIV LAV-03 (AIDS Research and Reference Reagent Program, NIH, Bethesda, MD, USA) is cultured in A 3.01 cells. The titre is determined in a reverse transcriptase assay. For the batch used it is 2 ~ 107 IV/ml.
' 40,000 exponentially growing MT-2 cells in 50 ~l of culture medium are introduced into each of the wells in a 96 round-base titre plate. The compounds to be investigated are added at the given concentration in 50 ~l of culture medium and, immediately thereafter, HIV in 100 ~l of culture medium is added. 100 ~l of culture medium without HIV are added to comparison samples. The titre plates are incubated for six days. The viability of the HIV-infected cells and the comparison cells is then tested in an MTT assay: the MTT assay relies on the reduction of yellow-coloured 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sigma, St. Louis, ~SA) by mitochondrial dehydrogenases of meta-bolically active cells to a blue formazan which can be measured spectro-photometrically at 540 nm (J. Virological Methods 20, 309 (1988)). The r-~-200~5i337 viability of compa}ison cells and HIV-infected cells is also determined microscopically in a haemocytometer according to the trypan blue exclusion method.

The investigated compounds of the preceding Examples exhibit a protective action against HIV infection at concentrations of 10 mol/litre.

'.''`"'.."", ; ..' ""`'`." :',' '`''''''',, .' "' ''':~-."~
. :"..

.'',;;'.'', ~"'"' : ,: .
`''~.'.~' : :::;~.::
',~"' "'.:' ., .~;:
,: :: ~--

Claims

1. Method of inhibiting the activity of gag protease in a warm-blooded animal, comprising administering to a said animal in need thereof a gag protease inhibiting amount of a compound of the renin inhibitor type or a related aspartate proteinase inhibitor.

2. Method according to claim 1, comprising administering a compound that exhibits inhibitory effects of 50 % or more when used at concentrations of 10 mol/l or less against gag protease in the form of an isolated enzyme or when used at concentrations of 10 5 mol/l or less against gag protease in the cell.

3. Method according to claim 2, wherein a compound of the formula wherein MN is a bivalent radical, consisting of from one to five bivalent .alpha.-amino acid residues, which is bonded N-terminally to the radical R2 and C-terminally to the radical Q, AAC is a bond or a bivalent radical, consisting of from one to five bivalent .alpha.-amino acid residues, which is bonded N-terminally to the radical Q and C-terminally to the radical R1, R1 is hydroxy, etherified hydroxy, amino or substituted amino with the exception of an amino radical derived from an .alpha.-amino acid, R2 is hydrogen or an acyl radical with the exception of an unsubstituted or N-substituted acyl radical of a natural amino acid, and Q is a bivalent radical that is an isostere of a dipeptide, or a salt of such a compound is administered.

4. Method according to claim 3, wherein, in a compound of the formula I, Q is a partial structure selected from among the formulae (IIa) (IIb) (IIc) (IId) (IIe) (IIf) (IIg) (IIh) (IIi) (IIj) (IIk) (IIl) (IIm) (IIn) (IIo) (IIp) (IIq) and (IIr) wherein free valencies that are not bonded to AAN or AAC are, independ-ently of one another, satisfied by hydrogen, unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tri-cycloalkyl or cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl or aryl-lower alkenyl, unsubstituted or substituted heteroaryl or heteroaryl-lower alkyl, unsubstituted or substituted hydroxy or by unsub-stituted or substituted amino and/or wherein free valencies at adjacent N
and C atoms are bridged by lower alkylene.

5. Method according to claim 4, wherein, in one of the formulae IIa to IIr, the free valencies that are not bonded to AAN or AAC are so satis-fied and/or bridged that the resulting isosteres correspond to the dipeptide radicals leucine-valine, phenylalanine-valine, cyclohexyl-alanine-valine, leucine-alanine, cyclohexylalanine-alanine, leucine-glycine, cyclohexylalanine-glycine, tyrosine-proline, phenylalanine-proline or cyclohexylalanine-proline.

6. Method according to claim 4, wherein, in one of the formulae IIa to IIr, the free valencies that are not bonded to AAN or AAC are so satis-fied by hydrogen, lower alkyl and/or by cyclohexylmethyl that the resulting isosteres correspond to the dipeptide fragments leucine-valine or cyclohexylalanine-valine.

7. Method according to claim 3, wherein, in a compound of the formula I, the radical AAN has two or more .alpha.-amino acid residues or the radical AAN
consists of only one amino acid residue and at the same time the radical R2 is an analogue of phenylalanyl.

8. Method according to claim 3, wherein, in a compound of the formula I, the radical AAC has two .alpha.-amino acid residues or the radical AAC consists of only one amino acid residue and at the same time the radical R1 is an analogue of the residue, bonded via the nitrogen, of the amino acid tyrosine.

9. Method according to claim 4, wherein, in a compound of the formula I, Q is a radical of the partial formula (IId) (IIe) or (IIm) wherein free valencies that are not bonded to AAN or AAC are, independ-ently of one another, satisfied by hydrogen, lower alkyl, aryl-lower alkyl or by cycloalkyl-lower alkyl and/or free valencies at adjacent N
and C atoms are bridged by lower alkylene.

10. Method according to claim 9, wherein, in one of the formulae IId, IIe and IIm, the free valencies that are not bonded to M N or AAC are so satisfied and/or bridged that the resulting isosteres correspond to the dipeptide radicals leucine-valine, phenylalanine-valine, cyclohexyl-alanine-valine, leucine-glycine, cyclohexylalanine-glycine, tyrosine-proline, phenylalanine-proline or cyclohexylalanine-proline.

11. Method according to claim 1 of treating diseases caused by retro-viruses in a warm-blooded animal comprising administering to a said warm-blooded animal in need thereof an anti-retrovirally effective amount of a compound of the renin inhibitor type or a related aspartate pro-teinase inhibitor.

12. Method according to claim 11, comprising administering a compound that exhibits inhibitory effects of 50 % or more when used at concentra-tions of 10 6 mol/l or less against gag protease in the form of an isolated enzyme or when used at concentrations of 10 5 mol/l or less against gag protease in the cell.

13. Method according to claim 12, wherein a compound of the formula wherein M N is a bivalent radical, consisting of from one to five bivalent .alpha.-amino acid residues, which is bonded N-terminally to the radical R2 and C-terminally to the radical Q, AAC is a bond or a bivalent radical, consisting of from one to five bivalent .alpha.-amino acid residues, which is bonded N-terminally to the radical Q and C-terminally to the radical R1, R1 is hydroxy, etherified hydroxy, amino or substituted amino with the exception of an amino radical derived from an .alpha.-amino acid, R2 is hydrogen or an acyl radical with the exception of an unsubstituted or N-substituted acyl radical of a natural amino acid, and Q is a bivalent radical that is an isostere of a dipeptide, or a salt of such a compound is administered.

14. Method according to claim 13, wherein, in a compound of the formula I, Q is a partial structure selected from among the formulae (IIa) (IIb) (IIc) (IId) (IIe) (IIf) (IIg) (IIh) (IIi) (IIj) (IIk) (IIl) (IIm) (IIn) (IIo) (IIp) (IIq) and (IIr) wherein free valencies that are not bonded to AAN or AAC are, independ-ently of one another, satisfied by hydrogen, unsubstituted or substituted lower alkyl, lower alkenyl, lower alkynyl, mono-, bi- or tri-cycloalkyl or cycloalkyl-lower alkyl, unsubstituted or substituted aryl, aryl-lower alkyl or aryl-lower alkenyl, unsubstituted or substituted heteroaryl or heteroaryl-lower alkyl, unsubstituted or substituted hydroxy or by unsub-stituted or substituted amino and/or wherein free valencies at adjacent N
and C atoms are bridged by lower alkylene.

15. Method according to claim 14, wherein, in one of the formulae IIa to IIr, the free valencies that are not bonded to AAN or AAC are so satisfied and/or bridged that the resulting isosteres correspond to the dipeptide radicals leucine-valine, phenylalanine-valine, cyclohexyl-alanine-valine, leucine-alanine, cyclohexylalanine-alanine, leucine-glycine, cyclohexylalanine-glycine, tyrosine-proline, phenylalanine-proline or cyclohexylalanine-proline.

16. Method according to claim 14, wherein, in one of the formulae IIa to IIr, the free valencies that are not bonded to AAN or AAC are so satisfied by hydrogen, lower alkyl and/or by cyclohexylmethyl that the resulting isosteres correspond to the dipeptide fragments leucine-valine or cyclohexylalanine-valine.

17. Method according to claim 13, wherein, in a compound of the formula I, the radical M N has two or more .alpha.-amino acid residues or the radical M N consists of only one amino acid residue and at the same time the radical R2 is an analogue of phenylalanyl.

18. Method according to claim 13, wherein, in a compound of the formula I, the radical M C has two .alpha.-amino acid residues or the radical M C consists of only one amino acid residue and at the same time the radical R1 is an analogue of the residue, bonded via the nitrogen, of the amino acid tyrosine.

19. Method according to claim 14, wherein, in a compound of the formula I, Q is a radical of the partial formula (IId) (IIe) or (IIm) wherein free valencies that are not bonded to AAN or M C are, independ-ently of one another, satisfied by hydrogen, lower alkyl, aryl-lower alkyl or by cycloalkyl-lower alkyl and/or free valencies at adjacent N
and C atoms are bridged by lower alkylene.

20. Method according to claim 19, wherein, in one of the formulae IId, IIe and IIm, the free valencies that are not bonded to AAN or AAC are so satisfied and/or bridged that the resulting isosteres correspond to the dipeptide radicals leucine-valine, phenylalanine-valine, cyclohexyl-alanine-valine, leucine-glycine, cyclohexylalanine-glycine, tyrosine-proline, phenylalanine-proline or cyclohexylalanine-proline.