CA2013475A1 - Amino acid derivatives - Google Patents

Abstract

Abstract The compounds of the formula I

wherein A. R1, R2, R3, R4 ,R5 and n have the significance given in claim 1, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof inhibit the activity of the natural enzyme renin and can accordingly be used in the form of pharmaceutical preparations in the control or prevention of high blood pressure and cardiac insufficiency. They can be manufactured according to various methods which are known Per se.

Description

2 ~

The present invention relates to amino acid derivaeives. In particular, it i5 concerned with amino acid derivatives of the general formula ~N~ (CH2)n--F

wherein Rl signifie6 hydrogen or methyl, R
signifies ethyl, propyl, isopropyl, imidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, thiazol-~-yl, thien-2-yl, ethoxycarbonyl, t-butylcarbonylmethyl. benzyloxy-carbonylmethyl or t-butoxy, R signifie6 isobutyl, cyclohexylmethyl or benzyl, R signifies hyd~oxy or amino, R signifies alkyl, haloalkyl, cycloalkyl, alkenyl, aryl or heteroaryl, n signifies 0, 1, 2, 3, 4, 5 or 6 and A signifies one of the groups R6 ~ (a, and -y-z (b) in which the dotted line can signify an additional bond, R signifies phenyl, substituted phenyl, benzyl or naphthyl and R ignifies hydrogen, alkoxycarbonylalkyl, alkylcarbonylalkyl, cycloalkyl-carbonylalkyl, heterocycloalkylcarbonylalkyl, aryl-carbonylalkyl, aminocarbonylalkyl, substituted amino-Kbr/20.2.90 7 ~

carbonylalkyl, aminoalkylcarbonylalkyl, substituted aminoalkylcarbonylalkyl, aminoalkylsulphonylalkyl, substituted aminoalkyl6ulphonylalkyl, alkoxycarbonyl-hydroxyalkyl, alkylcarbonylhydroxyalkyl, cycloalkyl-carbonylhydroxyalkyl, heterocycloalkylcarbonylhydroxy-alkyl, arylcarbonylhydroxyalkyl, aminocarbonylhydroxy-alkyl, substituted aminocarbonylhydroxyalkyl, dialkoxypho~pho~oxyalkyl, diphenyloxyphosphoroxyalkyl,-arylalkyl, alkoxycarbonylamino, arylalkoxycarbonyl-amino, alkylthioalkyl, alkylsulphinylalkyl, alkyl-sulphonylalkyl, arylthioalkyl, arylsulphinylalkyl, arylsulphonylalkyl, arylalkylthioalkyl, arylalkyl-sulphinylalkyl or arylalkylsulphonylalkyl, Y signifies the bivalent residue of optionally N- and/or a-methylated phenylglycine, cyclohexylglycine, phenylalanine, cyclohexylalanine, 4-fluorophenyl-alanine, 4-chlorophenylalanine, tyrosine, 0-methyl-tyrosine, a-naphthylalanine or homophenylal~nine linked with Z at the N-terminal and Z signifiPs hydrogen or acyl, with the p~ovisos that ti) R does not signify alkyl, cycloalkyl or aryl where n signifies 2, 3, 4, 5 or 6, (ii) the carbon atom of alkyl which is attached to the CH2 g~oup is branched where n signifies 1 and R5 signifies alkyl, (iii) the carbon atom of R5 attached to the carbon atom ca~rying the ubstituent R
has no methylene group in the a-position where n signifies 0 and R5 signifies alkyl, (iv) R does not signify alkyl where R2 signifies imidazol-4-yl, R4 signifies hydroxy and Y signifies phenylalanine and (v) R does not signify alkoxycarbonylamino or arylalkoxycarbonylamino where R signifies phenyl, benzyl or a-naphthyl, in the form of optically pure diastereomers, mixturas of diastereomers, diaste~eomeric racemates or mixtures of diaste~eomeric ~acemates as well as pharmaceutically usable salts of these compounds.

These compounds are novel and a~e distinguished by valuable pharmacodynamic properties.

Objects of the present invention ace the compounds of formula I and thei~ pharmaceutically usable salts per se and for use as therapeutically active substances, the manufacture o~ these compounds, medicaments containing these and the manufacture of such medicaments, as well as the use of compounds of formula I and their pharmaceu-tically usable salts in the control or prevention of illnesses or in the improvement of health, especially in the control or prevention of high blood pressure and cardiac insufficiency.

The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appea~ alone or in combination.

The tsrm ~'alkyl" used in the present description signifies straight-chain and branched, saturated hydro-carbon residues with 1-8, preferably 1-4, carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, t-butyl, pentyl, hexyl and the like.
The term "alkoxy" signifies alkyl ethec groups in which the term "alkyl" has the above significance, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.-butoxy, t-butoxy and the like. The ~erm "cycloalkyl"
signifies saturated, cyclic hydrocarbon residues wi~h 3-8, preferably 3-6, carbon atoms such as cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl and the like. The term "heterocycloalkyl" relates in the same manner to 7~

saturated, 3-8-membered, preferably 5- or 6-membered, cyclic hydrocarbon residues in which one or two methylene groups is/are replaced by one or two oxygen, sulphur or optionally alkyl-, phenylalkyl-, alkanoyl- or alkanoyloxy-substituted nitrogen atoms, such as piperidinyl, eyrazinyl, N-benzyl-pyrazinyl, morpholinyl, N-methylpiperidinyl, N-benzylmor-pholinyl and the like. The term "haloalkyl" signifies alkyl in which a hydrogen atom is replaced by halogen. The term "alkenyl~ relates to straight-chain and branched unsaturated hydrocarbon residues with 2-8, preferably 2-4, carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 3-pentenyl and the like. The term "halogen" relates to the four halogens fluorine, chlorine, bromine and iodine. The term "alkanoyl"
signifies the acid residue of a straight-chain or branched alkanoic acid with 1-8, preferably 1-4, carbon atoms such as formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl and the like. The term "aryl" denotes a mono- or bicyclic aromatic hydrocarbon residue with 6-14 carbon atoms which is optionally mono- or multiply-substituted by alkyl, alkoxy, 20 alkanoyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl-amino, hydroxy, halogen, trifluoromethyl or nitro, such as phenyl, - or ~-naphthyl, indenyl, anthryl or phen~
anthryl and the like. The term "arylalkyl" denotes straight-chain or branched alkyl groups in which one or 2~ more hydrogen atoms is/are reelaced by aryl groups, such as benzyl, diehenylmethyl, trityl, a- or ~-naphthylmeth~l, 2-phenylethyl, 3-phenyl-2-propyl, 4-phenyl-3-butyl, 2-~a- or ~-naphthyl)ethyl, 3-a-naphthyl-2-propyl, 4--naphthyl-3-butyl and the like, whereby the aromatic 30 residue can in each case be mono- or multiply-substituted as indicated above. The term ~substituted phenyl~ denotes phenyl which is optionally mono- or multiply-substituted by alkyl, alkoxy, alkoxyalkoxy, alkanoyl, alkanoyloxy, hydroxy, halogen or trifluoromethyl, such as 35 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 2~3~

4-chlorophenyl, 4-ethoxyethoxyphenyl and the like. The term ~'heteroaryl~ denotes a mono- or bicyclic aromatic hydrocarbon cesidue in which one or more carbon atoms is/are replaced by one or two nitrogen atoms and/or an oxygen or sulphur atom and which is optionally substituted on a nitrogen atom by alkyl, phenyl or phenylalkyl and/or on one or more carbon atoms by alkyl, phenyl, phenylalkyl, halogen, hydroxy, alkoxy, phenylalkoxy or oxo and which can be partially saturated, such as pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl or quinoxalinyl, e.g. 2- or 3-py~rolyl, phenylpyrrolyl, e.g. 4- or ~-phe~yl-2-pyrrolyl, 2-furyl, 2-thienyl, 2-imidazolyl, 2-, 3- or 4-pyridyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, fGr example l-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, S-chloro or 4,5-dimethyl-2-indolyl, 1-benzyl-2-indolyl, 1-benzyl-3--indolyl, ~,5,6,7-tetrahydro-2-indolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, l-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzo-furanyl, 2-benzoxazolyl, 2-benzthiazolyl and the li~e.

The term l'substituted amino" signifies an amino group which is mono- or di-substituted by alkyl, arylalkyl, alkanoyl, alkoxycarbonyl or arylalkoxycacbonyl or disubstituted by C3-C6-alkylene which is optionally interrupted by an oxygen, sulphur or optionally alkyl-~
phenylalkyl-, alkanoyl- or alkanoyloxy-substituted nitrogen atom. The term "acyl" relates to the acyl group o~ a carboxylic acid, of a half ester of carbonic acid, of an optionally N-substituted carbamic or thiocarbamic acid, of an optionally N-substituted oxalamide, of a sulphonic acid or of an optionally N-substituted amidosulphonic acid, especially those with the partial formulae R -C0-, Ra-0-C0-, (Rb)(Rb)N-C0-, (R )(R )N-CS-, (R )(R )N-C0-C0-, R -S02- or (R )(Rb)N-S02-, 2 ~ 7 ~

in which Ra signifies an unsubstituted or substitutea, saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic hydrocarbon residue with up to 18, preferably 10, carbon atoms which is optionally functionali2ed with amino, monoalkylamino, dialkylamino, alkanoylamino or alkanoyloxyamino, an unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon residue with up to 18, preferably 10, carbon atoms or an unsubstituted or substituted, saturated 5- or 6-membered heterocyclic residue and R signifies hydrogen or has the significance of R . The term "acyl" also relates to the monovalent residue of an optionally acylated amino acid or of an optionally acylated dipeptide attached via the carboxyl group.

An unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic or cycloaliphatic--aliphatic hydrocarbon residue R or R is, for example, unsubstituted or substituted alkyl, alkenyl, alkynyl, mono-, bi- or tricycloalkyl, monocycloalkenyl, bicycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkenylalkyl. "Substituted alkyl" signifies an alkyl residue in which one or more hydrogen toms can be substituted by hydroxy, alkoxy, aryloxy, alkanoyloxy, halogen, hydroxysulphonyloxy, carboxy. alkoxycarbon~l, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, phosphono, esterified phosphono, amino or oxo, whereby the substituents are present in the l-position of the alkyl residue only when this is a~tached to the carbonyl group in the partial formula ~ -C0-.

Examples of substituted alkyl are 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, phenoxymethyl, ~- or ~-naphtho~ymethyl, acetoxymethyl, Z-acetoxyethyl, chloro-methyl, bromomethyl, 2-chloro- or 2-bromoethyl, hydroxy-20~3~

sulphonyloxymethyl, 2-hydroxysulphonyloxyethyl, carboxy-methyl, ~-carboxyethyl, methoxycarbonylmethyl, 2-methoxy-carbonylethyl, ethoxycarbonylmethyl, 2-ethoxycarbonyl-ethyl, carbamoylmethyl, 2-carbamoylethyl, methylcarbamoyl-methyl, dimethylcarbamoylmethyl, cyanomethyl, 2-cyano-ethyl, 2-oxopropyl, 2-oxobutyl, hydroxycarboxymethyl, l-hydroxy-2-carboxyethyl, hydroxyethoxycarbonylethyl, hydrox~methoxycarbonylethyl, acetoxymethoxycarbonylmethyl, 1,2-dihydroxy-2-carboxyethyl, 1,2-dihydroxy-2-ethoxy-carbonylethyl, l,2-dihydroxy-2-methoxycarbonylethyl, 1,2-diacetoxy-2-ethoxyca~bonylethyl, 1,2-diacetoxy-2--methoxycarbonylethyl, l-~-naphthoxy-3-carboxyp~opyl, 1--naphthoxy-2-ethoxyca~bonylethyl, 1-a-naphthoxy-3- --t-butoxycarbonylpropyl, l-a-naphthoxy-2-benzyloxy-carbonylethyl, l-a-naphthoxy-3-carbamoylpropyl, -naphthoxycyanomethyl, l-a-naphthoxy-3-cyanopropyl, l--naphthoxy-4-dimethylaminobutyl or 1-a-naphthoxy-3--oxobutyl.

The term "alkenyl" relates to an unsaturated hydro-carbon residue such as has been defined above, whereby the double bond can be present in the l-position of the alkenyl residue only when this is attàched to the carbonyl group in the partial formula R -C0-. The alkenyl residues can be substituted by the same substi~uents as the alkyl residues.

The term "alkynyl" relates to hydrocarbon residues with 2-8, preferably 2-4, carbon atoms which contain a triple bond, such as ethynyl, l-propynyl or 2-propynyl.
The term "bicycloalkyl" relates to bicyclic saturated hydrocarbon residues with 5-10, preferably 6-9, caebon 35 atoms such as bicyclo[3.1.0]hex-1-yl, bicyclor3.1.0]hex-2--yl, bicyclor3.1.0]hex-3-yl, bicyclor4.1.0]hept-1-yl.
bicyclor4.1.0]hept-4-yl, bicyclor2.2.1]hept-2-yl, bicyclo-r 3.2.1]oct-2-yl, bicyclo r 3.3.0]oct-3-yl, bicyclo r 3.3.1]-non-9-yl, a- or ~-decahydronaphthyl and the like.

2~3~

The term "tricycloalkyl" relates to a tricyclic saturated hydrocarbon residue with 8-10 carbon atoms such as l-adamantyl.

The term "cycloalkenyl~ relates to an unsaturated cyclic hydrocacbon residue with 3-8, p.eferably 3-6, carbon atoms such as l-cyclohexenyl, 1,4-cyclohexadienyl and the like.

The term "bicycloalkenyl" relates to a bicyclic unsaturated hydrocarbon residue with 5-10, preferably 7-10 carbon atoms ~uch as 5-norbornen-2-yl, bicyclot2.2.2]-octen-2-yl, hexahydro-4,7-methanoind-1-en-6-yl and the like.

Cyclopropylmethyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexylmethyl and the like are examples of cycloalkylalkyl. Cyclohexylvinyl and cyclohexylallyl and the like can be named as examples of cycloalkylalkenyl.
l-Cyclohexenylmethyl, l,~-cyclohexadienylmethyl and the like are examples of cycloalkenylalkyl.

The mentioned cycloaliphatic and cycloaliphatic--aliphatic residues can be substituted by the same substituents as alkyl.

An optionally substitu~ed aromatic or aromatic--aliphatic hydrocarbon residue is, for example, unsubstituted or substituted aryl, arylalkyl or aryl-alkenyl. Styryl, 3-phenylallyl, 2-(a-naphthyl)vinyl, 2-(B-naphthyl)vinyl and the like are examples of aryl-alkenyl.

In a heteroaromatic or heteroaromatic-aliphatic hydro-carbon residue the heterocycle is mono-, bi- or tricyclic and contains one or two nitrogen atoms and/or an oxygen or 2 ~ 7 ~

sulphur atom and is linked ~ith the group -C0-, -0-C0-, >N-C0-. >N-CS-, >N-C0-C0-, -S02 or >N-502- with one of its ring carbon atoms. Examples of such heteroaromatic hydrocarbon residues are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, B-carbolinyl or a benz-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these residues. The heteroaromatic residue can be substituted sn a nitrogen atom by alkyl, phenyl or phenylalkyl, e.g.
benzyl, and/or on one or more ca~bon a~oms by alkyl, phenyl, phenylalkyl, halogen, hydroxy, alkoxy, phenyl-alkoxy or oxo and can be partially saturated. Examples ofsuch heteroaromatic residues are 2- or 3-pyrrolyl, phenyl-pyrrolyl, e.g. 4- or 5-phenyl-2-pyrrolyl, 2-~uryl, 2-thienyl, 2-imidazolyl, 2-, 3- or 4-pyridyl, 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-indolyl, 1-benzyl-3--indolyl, 4,5,6,7-tetrahydro-~-indolyl, cycloheptarb]-5--pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-~enzoxazolyl, 2-benz-thiazolyl, benz[e]indol-2-yl, ~-carbolin-3-yl and the like.

Examples of heteroaromatic-alipha~ic hydrocarbon residues are 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridyl-methyl, Z-(2-, 3- or 4-pyridyl)ethyl, 4-imidazolylmethyl, 2-(4-imidazolyl)ethyl, 2-indolylmethyl, 3-indolylmethyl, 2-(3-indolyl)ethyl, 2-quinolylmethyl and the like.

A saturated 5- or 6-membered heterocyclic residue has at least one carbon atom, 1-3 nitrogen atoms and optionally an oxygen or sulphur atom as the ring members and is linked with the group -C0- or -0-C0-, >N-C0-, >N-CS-, >N-C0-C0-, -S02- or >N-S02- wi~h one of its 2 ~ ~ 3 ~

ring carbon atoms. The heterocycle can be substituted on one of its carbon atoms or on a ring nitrogen atom by alkyl, e.g. met~yl or ethyl, phenyl or phenylalkyl, e.g.
benzyl, or on one of its carbon atoms by hydroxy or oxo and/or can be benz-fused on two adjacent carbon atoms.
Examples of such residues are pyrrolidin-3-yl, 4-hydroxy-pyrrolidin--2-yl, 5-oxo~yrrolidin-2-yl, piperidin-2-yl, piperidin-3-yl, 1-methyleiperidin-2-yl, l-methylpiperidin--3-yl, 1-~ethylpiperidin-4-yl, morpholin-Z-yl, morpholin--3-yl, thiomorpholin-~-yl, thiomorpholin-3-yl, 1,~-dimethylpiperazin-2-yl, 2-indolinyl, 3-indolinyl, 1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl, 1,2,3,9-tetra-hydroisoquinol-l-, -3- or -4-yl, 1-oxo-1,2,3,~-tetrahydro-isoquinol-3-yl and the like.

As residues of an amino acid attached via the carboxyl group there come into consideration natural a-amino acids having the L-configuration, homologues of such amino acids, e.g. in which the amino acid side-chain is lengthened or shortened by one or two methylene groups and/or a methyl group i6 replaced by hydrogen, substituted aromatic a-amino acid~, e.g. substituted phenylalanine or phenylglycine in which the substituent can be alkyl, e.g. methyl, halogen, e.g. fluorine, chlorine, bromine or iodine, hydroxy, alkoxy, e.g. methoxy, alkanoyloxy, e.g.
acetoxy, amino, alkylamino, e.g. methylamino, dialkyl-amino, e.g. dimathylamino, alkanoyla~ino, e.g. acetylamino or pivaloylamino, alkoxycarbonylamino, e.g. t-butoxy-carbonylamino, arylmethoxycarbonylamino, e.g. benzyloxy-carbonylamino, and/or nitro and can be present singly oc multiply, benz-fused phenylalanine or phenylglycine such as a-naphthylalanine or hydrogenated phenylalanine or phenylglycine such as cyclohexylalanine or cyclohexyl-glycine, a 5- or 6-membered cyclic benz-fused a-amino acid, e.g. indoline-2-carboxylic acid or 1,2,3,~-tetra-hydroisoquinoline-3-carboxylic acid, a natural or ~ 3 homologous -amino acid in which a carboxy group in the side-chain i6 present in esterified or amidated form, e.g.
as an alkyl ester group such as methoxycarbonyl or t-butoxycarbonyl or as a carbamoyl group, as an alkyl-carbamoyl group such as methylcarbamoyl or as a dialkyl-carbamoyl group such as dimethylcarbamoyl, in which an amino group of the side-chain is present in acylated form, e.g. as an alkanoylamino group such as acetylamino or pivaloylamino, as an alkoxycarbonylamino group such as t-butoxycarbonylamino or as an arylmethoxycarbonylamino group such as benzyloxycarbonylamino, or in ~hich a hydroxy group of the side-chain is present in etherified or esterified form, e.g. as an alkoxy group ~uch as methoxy, as an arylalkoxy group such as benzyloxy or as a lower alkanoyloxy group such as acetoxy, or epimers of such amino acids, i.e. with the unnatural D-configuration.
Examples of such amino acids are glycine, alanine, valine, norvaline, leucine, isoleucins, norleucine, serine, homoserine, threonine, methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-nitrophenylalanine, 4-aminophenylalanine, 4-chlorophenylalanine, ~-phenyl~erine, phenylglycine, -naphthylalanine, cyclohexylalanine, cyclohexylglycine, tryptophane, indoline-2-carboxylic acid, ~,2,3,4-te~ra-25 hydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomalonic acid, aminomalonic acid mono-amide, glutamic acid, glutamic acid mono-t-butyl ester, glutamine, N-dimethylglutamine, histidine, arginine, lysine, N-t-butoxycarbonyllysine, ~-hydroxylysine, 30 ornithine, N-pivaloylornithine, ~,y-diaminobutyric acid or ,~-diaminopropionic acid and the like. The residue of the amino acid attached via the carboxyl group can be substituted N-terminally by alkyl, e.g. me~hyl or ethyl, in order to increase the stability of the compound 35 of formula I against enzymatic degradation.

The residue of a dipeptide attached via the carboxyl group consists of two of the above-mentioned amino acids, The term "acylated amino acid" or "acylated dipeptide"
relates to one of the above-mentioned amino acids or to a dipeptide from two of the above-mentioned amino acids which is N-terminally substituted by the acyl residue of a carboxylic acid, of a half ester of carbonic acid, of an optionally N-substituted caIbamic or thiocarbamic acid, of an optionally N-substituted oxalamide, of a sulphonic acid or of an optionally N-substituted amidosulphonic acid.

The term "pharmaceu~ically usable salts" embraces salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulphonic acid, p-toluenesulphonic acid and the like. Such salts can be manufactured readily by any person skilled in the art having regard to the state of the art and taking into consideration the nature of the compound to be converted into a salt.

The compounds of formula I have at least three asymmetric carbon atoms and aee therefore present in ~he form of optically pure dias~ereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. The pEesent invention embraces all forms. Mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates can be separated according to usual methods, e.g. by column chromatography, thin-layer chromatography, HPLC and the like.

Those compounds of formula I in which Rl signifies hydrogen are preferred. R2 preferably signifies 2al3~

imidazol-2-yl, imidazol-4-yl or thiazol-9-yl, particularly imidazol-4-yl. Further, those compounds of formula I in which R3 signifies cyclohexylmethyl are preferred. R4 preferably signifies hydroxy. Those compounds ~f formula I
in which R5 signifies alkyl, preferably 3-pentyl, halo-alkyl, preferably fluoroalkyl, cycloalkyl, preferably cyclohexyl, or alkenyl, preferably 3-pentenyl, are also preferredO The preferred significance of n is 0 or 1, particularly 1. The compounds of formula I in which ~
signifies group (a) are also preferred. R preferably signifies phenyl or substituted phenyl, particularly phenyl. The preferred significance of R is alkyl-carbonylalkyl, aminoalkylcarbonylalkyl, substitutedaminoalkylca~bonylalkyl, aminoalkylsulphonylalkyl, substituted aminoalkylsulphonylalkyl or alkylsulphonyl-alkyl, preferably alkylca~bonylalkyl or alkylsulphonyl-alkyl, particularly Cl-C4-alkylcarbonylmethyl or Cl-C4-alkylsulphonylmethyl. Where A signifies group (b), then there are preferred those compounds of formula I
in which Y signifies the bivalent residue of phenylalanine linked with Z at the N-terminal. Z pIeferably signifies the group R -0-C0- or the residue of an a-amino acid, preferably proline, acylated by this group, wherein R
signifies an optionally substituted, saturated aliph~tic hydrocarbon residue with up to 10 carbon atoms or an optionally subs~ituted heteroaromatic hydrocarbon residue with up to 18 carbon atoms, particularly a saturated, aliphatic hydrocarbon residue with up to 6 carbon atoms.

From the above it follows that there are particularly preferred those compounds of formula I in which R
signifies hydrogen, R signifies imidazol-4-yl, R
signifies cyclohexylmethyl, R signifies hydroxy, R
signifies 3-pentyl, ~luoroalkyl, cyclohexyl or 3-pentenyl, n signifies 1, R signifies phenyl, R signifies Cl-C4-alkylcarbonylmethyl or Cl-C4-alkylsulphonyl-~ 3~7~

methyl, Y signifies the bivalent residue of phenylalanine linked with Z at the N-terminal and Z signifies the group R -0-C0- or the residue of proline which is acylated by thi~ group. wherein R signifies a saturated, aliphatic hydrocarbon residue with up to 6 carbon atoms.

Quite specially preferred compounds of formula I are:

t-Butyl (R)-2-r[(S~-a-t[(S)-l-rt(lS,2S,4R)-l-(cyclo-hexylmethyl)-~-hydroxy-4-ethyl-5-hexenyl]carbamoyl]-Z--imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1--pyrrolidinecarboxylate, t-butyl (R)-2-t~(S)-a- r [ (S)-l-[[(lS,2S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-e~hylhexyl]carbamoyl]-2-imidizol--4-ylethyl]carbamoyl]phenethyl]carbamoyl~-1-pyrrolidine-carboxylate, (S)-N-[(lS,2S,4R)-l-(cyclohexylmethyl)-4-ethyl-2--hydroxy-5-hexenyl]-a-[(R)-a-(3,3-dimethyl-2-oxobutyl)-hydrocinnamamido]imidazole-4-propionamide.
(S) -a- [ (S) -~- ~ ( t-butylsulphonyl)methyl]hydrocinnam-amido~-N- r (lS,ZS.4R)-l-(cyclohexylmethyl)-4-ethyl-2--hydroxy-5-hexenyl]imidazole-5-propionamide, t-butyl r (S)-a-[[(S)-l-[[(lS,2R or 2S)-3-cyclohexyl--l-(cyclohexylmethyl)-2-hydroxypropyl]carbamoyl]]-2--imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate, (2R or S,35)-3-(Boc-D-Pro-Phe-His-NH)-1,~-dicyclo-hexyl-2-butanol and (S)-N-[(lS,2S)-l-(cyclohexylmethyl)-4-ethyl-4-fluoro--2-hydroxyhexyl]-a-[(R)-a-(3,3-dimethyl-Z-oxo~utyl)-hydrocinnamamido]imidazole-4-propionamide.

The compounds of formula I in the form of optically pure diastereomers, mixtures of diastereomers, diastereo-meric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof can be manufactured by 2~3~7~J

a) for the manufacture of a compound of formula I in which R signifies hyd~oxy and the remaining symbols have the significance given above, reacting a compound of the genecal formula H~ ~ N ~ (CH2)n~ R5 II

wherein R , R , R , R and n have the significance given above, with an acylating agent yielding the group ~ (a) or -Y-Z (b) wherein R . R7. Y, Z and the dotted line have the significance given above.
or b) for the manufacture of a compound of formula I in which R signifies hydroxy and the remaining symbols have the significance given above. reacting a compound of the ge~neral formula H2N ~ (CH2)n- R~ III
0~

wherein R , R and n have the significance given above, with a compound of the general formula 1 ' o A ~ IV
~R2 wherein R , R and A have the significance given above, or an activated derivative thereof, or c) for the manufacture of a compound of formula I in which A signifies group (b), Z signifies the monovalent residue of an optionally acylated amino acid or of an optionally acylated dipeptide attached via the carboxyl group and R signifies hydroxy and the remaining symbols have the significance given above, reacting a compound of formula T in which Z signifies hydrogen and the remaining symbols have the significance given above with an optionally acylated amino acid or an optionally acylated dipeptide, or d) for the manufacture of a compound of formula I in which A ~ontains a free amino group and/or R4 signifies amino and/or R signifies imidazol-2-yl, imidazol-4-yl or pyrazol-3-yl, cleaving off the N-protecting group(s) from a corresponding compound of formula I in which A
contains a N-pro~ected amino group and/or from a compound of the general formula y~

Rl 5 A~N~(CH2)n--R V

~21 10 wherein R41 signifies hydroxy or N-protected amino and R signifies ethyl, propyl, isopropyl, thiaz~l--4-yl, thien-Z-yl, ethoxycarbonyl, t-butylcarbonyl-me~hyl, benzyloxycarbonylmethyl, t-butoxy or optionally N-protected imidazol--2-yl, imidazol-4-yl or pyrazol-3-yl.and the cemaining symbols have the significance given above, with the proviso that a~
least one of R and R contains a N-protecting group, and e) if desired, separating a mixture of dias~ereomeric racemates into the diastereomeric racemates or optically pure diastereomers, and/or f) if desired, separating a mixture of diastereomers into the optically pure diastereomers, and/or g) if desired, convarting a compound obtained into a pharmaceutically usable salt.
The acylation of a compound of formula II is effected acco~ding to methods known per se. Especially suitable acylating agents are activated acid derivatives such as esters, mixed esteLs, acid halides and acid anhydrides or mixed acid anhydrides. The reaction is carried ou~ in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0C

2 ~

and room temperature. As solvents there come into consideration especially aromatic hydrocarbons such as benzene, toluene or xylene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, tetrahydrofuran or dioxan, and the like.
Where the acylating agent is a peptide, the reaction is effected under reaction conditions which are usual in peptide chemistry, i.e. preferably in the presence of a condensation agent suc~ as HBTU (O-benzotriazolyl--N,N,N',N'-tetramethyluronium hexafluorophosphate), BOP
(benzotriazol-l-yloxy-bis-(dimethylamino)phosphonium hexa-fluorophosphate), BOPC (bis(2-oxo-2-oxozolidinyl)phosphine chloride), HOBT (N-hydro~ybenzotriazole), DBU (l,~-diaza-bicyclo[5.4.0]undec-7-ene), DCC (dicyclohexylcarbodi-imide), EDC (N-ethyl-N'(3-dimethylaminopropyl)carbodiimide hydrochloride), Hunig base (ethyldiisopropylamine), and the like. The reaction is conveniently carried out in an organic solven~ or solvent mixture which is inert under the reaction conditions at a temperature between about 0 and 50~C, preferably at about room temperature. As solvents there come into consideration especially dimethylformamide, methylene chloride, acetonitrile, tetrahydrofuran, and the like.

The reaction of a compound of formula III wi~h a compound of formula IV is also effected according to methods which are known per se in peptide chemistry, i.e.
under the same conditions as given above for the reaction of a compound of formula II with a peptide. Examples of suitable activated derivatives of a compound of formula IV
are acid halides, acid anhydrides, mixed anhydrides, esters, mixed esters~ and the like.

The reaction of a compound of formula I in which Z
si~nifies hydrogen with an optionally ac~lated amino acid or an optionally acylated dipep~ide in accordance with ~V~3~,7J' process variant c) is likewise effected according to methods which are known per se in peptide chemistry, i.e.
under the conditions given above for the reaction of a compound of formula II with a peptide.

The cleavage of the N-protecting group(s) in accordance with process variant d) is also effected according to methods known per se depending on the nature of the N protecting group to be cleaved o~f. However, the cleavage is conveniently effected by acidic or basic hydrolysis. For the acidic hydrolysis there i8 advantageously used a solution of a mineral acid such as hydrochloric acid, hydrobromic acid, trifluoroace~ic acid, sulphuric acid, phosphoric acid and the like in an inert solvent or solvent mixture. Suitable solvents are alcohols such as methanol or ethanol, ethers such as tetrahydro-furan or dioxan, chlorinated hydrocarbons such as methylene chloride, and the like. For the basic hydrolysis there can be used alkali metal hydroxides and carbonates such as potassium or sodium hydroxide or potassium or sodium carbonate, organic amines such as piperidine, and the li~e. Inert organic solvents such as have been named above for the acidic hydrolysis can be added as solubilize~s. The reaction temperature for the acidic and basic hydrolysis can be varied in a range from about O9C
to the reflux temperature, with the reac~ion preferably being carried out between about 0C and room temperature.
The ~-butoxycarbonyl residue is convenien~ly cleaved off with trifluoroacetic acid or formic acid in the presence or absence of an inert solvent. The Fmoc protecting group is conveniently cleaved off with piperidine at about room temperature. The benzyloxycarbonyl group can be cleaved off in a known manner by acidic hydrolysis as described above or hydrogenolytically.

~ 3 - 20 ~

The starting materials of formula II are novel and are also an object of the present invention. These compounds can be prepared by reacting a compound of formula III with optionally N-methylated histidine, leucine, norleucine, norvaline, thiazolylalanine, thienylalanine, aspartic acid ethyl ester, glutamic acid t-butyl ester, glutamic acid benzyl ester or t-butoxyserine. This reaction is also effected according to methods which are known in peptide chemistry, i.e. under the reaction conditions which are described above for the reaction of a compound of formula II with a dipeptide.

The starting materials of formula III are also novel and are an object of the present invention. They can be prepared, for example, by cleaving off the amino protecting group and, where applicable, simultaneously also the 0-protecting group in a compound of the general formula B-HN~(CH2)n--R51 o~ ~(cH2)n--Rs OH ~o V I V I I

wherein B signifies an amino protec~ing group, preferably t-butoxycarbonyl or benzyloxycarbonyl, and ~5l signifies alkyl, cycloalkyl, alkenyl, aryl or heteroaryl and R and R have the significance given above.

The cleavage of the W-protecting group and, where applicable, 0-protecting group is also effected according to methods known per se, for example in an organic solvent or solvent mixture which is inert under 2 ~ 7 ~

the reaction conditions at a temperature between about O~C
and room temperature with an acid such as hydrochloric acid, trifluoroacetic acid and the like. Suitable solvents are ethers such as tetrahydrofuran or dioxan, alcohols such as methanol or chlorinated hydrocarbons such as methylene chloride and the like. Under these reaction conditions the oxazolidine ring in a compound of formula VII is - as already mentioned - simultaneously cleaved.

The starting materials of formula IV are known or can be obtained in analogy to the preparation of the known compounds.

The compounds of formulae VI and VII are also novel and are an object of the present invention. The compounds of formula VI can be prepared, for example, by reduction of the corresponding keto compounds of the general formula B-HN ~ (CH2)n - R51 VIII

wherein B, R3 and R51 have the significance given above.

The reduction of a keto compound of formula VIII is also effected according to methods known per se, for 30 example with a complex metal hydride such as sodium borohydride and the like in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0C and about room temperature.

The compounds of formula VII in which R signifies alkyl, cycloalkyl, alkenyl, aryl or heteroaryl can be 2~ 7~

prepared, for example, by reac~ing a compound of formula VI with 2,2-dimethoxypropane in the presence of p-toluenesulphonic acid.

The compounds of formula VII in which R signifies haloalkyl can be p~epared, for example, by subjecting a compound of focmula VII in which R signifies aikenyl to a reductive or oxidative ozonolysis. The compound of the general formula R3 /R8~ R10 $~ 1R9~0H I X

whe~ein Ra, R9 and R each independently signify hydrogen or alkyl and m signifies 0, 1, Z, 3, 4, 5, 6 o~ 7, with the proviso that the group ~ R9m ~ R10 has a maximum of B carbon atoms, OH

and B, R and n have the above significance, which is obtained in the reductive ozonolysis can be converted with a halogenating agent into a compound of formula VII in which R5 signifies primary or secondary haloalkyl. The compound of the general formula ~(CHZ)n--(IC~COCI I X

wherein B, R , R , R9, n and m have the significance given above, which is obtained in the oxidative ozonolysis can be converted by reaction with, for example, diazsmethane into the corresponding methyl ester of the general formula ~ (CH2)n ~ ~ ~ COOCH3 XI
~0 wherein B, R3, R , R , n and m have the significance given above, which can be converted by reaction with a compound of the genecal fo~mula ~-Mg_Rll XII

wherein R 1 signifies alkyl and W signifies chlorine, bromine or iodine, preferably bromine, in a Grignard reaction into a compound of the general formula 20~3~7~

~(CH~n--(~OH Xl 11 wherein B, R3, R~, R9, Rll, n and m have the significance given above, with the proviso that the group R8\ R11 I ~ has a maximum of 8 carbon atoms.

This reaction is also effected according to methods known per se, for example in an inert solvent which is inert under the reaction conditions. such as an ether, at a temperature between about 0C and 50~C, preferably at room temperature-Reaction of a compound of formula XIII with a halogenating agent yields a compound of formula VII in which R signifies tertiary haloalkyl.

The starting materials of formula V are also novel and are an object of the present invention. Those in which R signifies N-p~otected imidazol-2-yl, imidazol-4-yl or pyrazol-3-yl can be prepared, for example, by reacting a compound of formula III with a compound of fo~muia IV, but in which R signifies N-protected imidazol-2-yl, imidazol-4-yl or pyrazol-3-yl 01 an activated derivative thereof. The reaction is effected according to methods which are known per se in peptide chemistry, i.e. under the same conditions as have been given above for the reaction of a compound of formula III with a compound of formula lV.

Those compounds of formula V in which R signifies N-protected amino can be ~repared, for example, by reacting a compound of the general formula 1 (CH2)n - R5 H2N ~ XIV

wherein R4 signifie6 N-protected amino and R , R and n have the significance given above, with a compound of formula IV. This reaction is also effected under the conditions given above for the reaction of a compound of formula III with a compound of formula IV.

The compounds of formula XlV are also novel and are an object of the pcesent invention. Those compounds of formula XIV in which R signifies alkyl, cycloalkyl, alkenyl, aryl or heteroaryl can be prepared, for example, by reacting a compound of focmula VIII with hydroxylamine to give a compound of the general formula 1 ~(CH2~n--R51 B-HN ~ XV

OH

- ~ v ~

wherein B, R3, R51 and n have the signif icance given above, reducing this to the corresponding amino compound of the general formula B-HN~ (CH2)n~ RS1 XV I

wherein B, R , R and n have ~he significance given above, and protecting the amino group with the formation of a compound of the general formula B-HN ~ (CH2)n - R51 XVII

wherein B R3 R42 R51 a d h th signiicance given above.
The co~Lesponding compound of formula ~IV is obtained by cleaving off the amino protecting group B und`er the conditions given for process variant d).

The compounds of formula XIV in which R signifies haloalkyl can be prepared from those compounds o~
formula XVII in which R signifies alkenyl in an analogous manner to that described above for the preparation of the compounds of formula VII in which R
signifies haloalkyl.

The compounds of focmulae VlII, IX, X, XI, Xll, XIII, XV, XVl, XVII, XVIII, XIX, XX, XXI, XXIl and XXlII are known or can be obtained in analogy to the preparation of the known compounds.

The various processes for the preparation of the compounds of focmulae III, V. VI and VII starting from compounds of formula XVIII are compiled in Scheme I
hereinafter. In this Scheme R52 signi~ies haloalkyl.
With respect to the precise reaction conditions as well as further preparative processes, reference is made to the experimental section.

2 0 ~ .3 8~NlCOOAI~

Scheme I
B HN~(CH2)n R5t vlll o U~NJ~U~n--R51 RJ B N~
XV N~ 6~N~C~i)n~ V~

~I N1~2 \ /~1 cH2)n--(7 ~( X

HN~CH~n ~ R n~ IC~W.--(~COOCH~

--(R)--( R3 \ \ ¦ Xll R ~

2 5 B N~ H2Jn--(~)--C~OCHl \ j ~I~/N~CH2)~--RS2 R3 ~ CH2)~--Rs2 XX ~42XX~ --(R ~C \

30\ ~ ~ /

~l~ H~)n RSH2N~(CH2h--RS

3 5 x,v \/ "~

R O R~
~H J~

The compounds of formula I and their pharmaceutically usable salts have an inhibitory activity on the natural enzyme renin. The latter passes from the kidneys into the blood and there brings about the cleavage of angio-tensinogen with the formation of the decapeptide angio-tensin I which is then cleaved in the lungs, the kidneys and other organs to the octapeptide angiotensin II. Angio-tensin II increases the blood pressure not only directlyby arterial constriction, but also indirectly by the liberation of the sodium ion-retaining hormone aldosterone from the adrenal gland, with which is associated an increase in the extracellular fluid volume. This increase is attributed to the action of angiotensin Il itself or ts the heptapeptide angiotensin III which is formed therefrom as a cleavage product. Inhibition of the enzymatic activity of renin brings about a decrease in the formation of angiotensin I and as a consequence thereof the formation of a smaller amount of angiotensin II. The reduced concentration of this active peptide hormone is the actual reason for the blood pressure-lowering activity of renin inhibitors.

The activity of renin inhibitors can be demonstrated experimentally by means of the in vitro test described hereinafter:

In vitro test with Pure human renin The test is carried out in Eppendorf test tubes. The incubation mixture consists of ~1) lO0 ~1 of hu~an renin in buffer ~ ~O.lM sodium phosphate solution, pH 7.g, containing 0.1~ bovine serum albumin, 0.1% sodium azide and l mM ethylenediaminetetraacetic acid), suf~icient for a renin activity of 2-3 ng of angiotensin I/ml/hr.; (2) 145 ~l of buffer ~; (3) 30 ~l of lO ~M human tetra-decapep~ide renin substrate (hTD) in lO mM hydrochloric acid: (4) 15 ~1 of dimethyl sulphoxide with or without 2~3~7~

_ 30 -inhibitor and (5) ~0 ~1 o~ a 0.03 molar solution of hyd~oxyquinoline sulphate in water.

The samples are incubated for three hours at 37C or 4C in triplicate. 2 x lO0 ~1 samples per experimental test tube are used in order to measure the production of angiotensin I via RIA (~tandard radioimmunoassay: clinical assay solid phase kit). Cross reactivities of the antibody used in the RIA are: angiotensin 1 100%; angiotensin II
0.0013%; hTD (angiotensin I-Val-Ile-His-Ser-OH) 0.09%. The production of angiotensin I is determined by the difference between the experiment at 37C and that at 4C.

The following controls are carlied out:

(a) lncubation of hTD sam~l0s without renin and without inhibitor at 37C and 4C. The difference between these two values gives the base value o~ angiotensin I
produ~tion.

(b) lncubation of hTD samples with renin, but without inhibitor at 37C and 4C. The difference between these values gives the maximal value of angiotensin I production.

In each sample the base value o~ the angiotensin I
production is subtracted from the angiotensin I production which is det-ermined. The difference between the maximal value and the base value gives the value of the maximal substrate hydrolysis (= 100%) by renin~

The results are given as IC50 values which denote that concentration of the inhibitor at which the enzymatic activity is inhibited by 50%. The IC50 values are determined from a linear regression curve from a logit-log plot.

~ 3~3 The results obtained in this test are compiled in the following Table:

Table Compound IC50 values in ~mol/lt.

10 A 0.0002 B 0.001 C 0.0042 D 0.001 E 0.0026 15 F 0.001 G 0.005 A = t-Butyl (R)-2-rr(S)-a-[r(S)-l-[ r (lS,2S,4R)-l-(cyclo-hexylmethyl)-2-hydroxy-4-ethyl-5-hexenyl]carbamoyl]-2--imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1--pyrrolidinecarboxylate, B = t-Butyl (R)-2-[r(S)-a-r~(S)-l-[[~lS,2S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-ethylhexyl]carbamoyl]-2-imidazol--4-ylethyl]carbamoyl]phenethyl]carbamoyl3-1-pyrrolidine-carboxylate, C - (S)-N-r(lS,2S,4E~-l-(Cyclohexylmethyl)-4~ethyl-2--hydroxy-5-hexenyl]-a-r(R)-a-(3,3-dimethyl-2-oxobutyl)-hydrocinnamamido]imidazole-4-propionamide, D = (S)-a- r (s)-a-r (t-bu~ylsulphonyl)methyl]hydrocinnam- -amido]-N-r(lS,2S,4R)-l-(cyclohexylmethyl)--4-ethyl-2--hydroxy-5-hexenyl]imidazole-5-propionamide, E = t-Butyl r(S)-a-r[(S)-l-rt(lS,2R or 2S)-3-cyclohexyl--l-(cyclohexylmethyl)-2-hydroxypropyl]carbamoyl3-2--imidazol-4-ylethylJcarbamoyl]~henethyl]carbamate, 2 ~ 7 F = (2R or S,3S)-3-(Boc-D-Pro-Phe-His-NH)-1,4-dicyclo-hexyl-2-butanol and G = (S)-N-t(lS,2S)-l-(Cyclohexylmethyl)-4-ethyl-4-fluoro--2-hydroxyhexyl~-a-[(R)-a-(3,3-dimethyl-2-oxobutyl)-hydrocinnamamido]imidazole-4-propionamide.

The compounds of formula I as well as their pharmaceu-tically usable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharma-ceutical preparations can be administered enterally such as orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or sus~ensions, nasally, e.g. in the form o nasal sprays, or rectally, e.g. in the form of suppositories. However, the ad~inistration can also be effected parenterally such as intramuscularly or intravenously, e.g. in the form of injection solutions.

For the manufacture of tablets, coated tablets, dragees and hard gelatine capsules the compounds of formula I as well as theic pharmaceutically usable salts can be prosessed with pharmaceutically inert, inorganic or organic excipients. Lactose, maize starch or derivatives th~reof, talc, stearic acid or its salts etc can be used e.g. as such excipients for tablets, dragees and hard gelatine capsules.

Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.

Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.

~J~3~7~

Suitable excipients for injection solutions are e.g.
water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable excipients for suppositocies are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.

Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers, viscosity-increasing substances, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, colouring agents, flavouring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.

ln accordance with the invention ~he compounds of general formula I as well as their pha~maceutically usable salts can be used in the control or prevention of high blood pcessure and cardiac insufLiciency. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration there should suf~ice a daily dofiage o~ about 3 mg to about 3 g, preferably about 10 mg to about 1 g, e.g. approximately 300 mg per person, divided in preferably 1-3 unit doses, which can e.g. be of the same amount, whereby, however, the upper limit just given can also be exceeded when this is found to be indicated. Usually, children receive half of the adult dosage.

The following Examples are intended to illustrate the presen~ invention, but are not intended to be limiting in any manner. All temperatures are given in degrees Celsius.
The following abbreviations are used:

7 ~

Boc = t-butoxycarbonyl Fmoc = 9-fluorenylmethoxycarbonyl H-His OH = L-histidine H-Phe-OH = L-phenylalanine H-D-Pro-OH = D-proline H-Phe-His-OH = N-[(S)-2-amino-3-phenylpropyl]--L-hi 6 tidine (Phe-His-NH? = L-phenylalaninyl-L-histidinamido (Fmoc)2His-OH = N--N-im-di-Fmoc-L-histidine Exam~le l To a solution of 227 mg (0.5 mmol) of (2)-a-amino-N--~(lS,2R or S)-l-(cyclohexylmethyl)-7-hydroxy-3-phenyl-propyl~imidazole-4-propionamide dihydrochloride in 2 ml of dimethylformamide while stirring and passing through argon at 0 there are added in ~he given sequence 151 mg of N-methylmorpholine, 1~6 mg sf Boc-Phe-OH and 208 mg of HBTU. Thereafter, the reaction mixture i~ allowed to warm 20 to room temperature and the pH is adjusted to 8.5 by the dropwise addition of N-methylmorpholine. After stirring a~
room temperature for 2 hours the reaction mixture ls poured into saturated sodium bicarbonate solution and stirred at room temperature overnight. Thereafter, the 25 mixture is extracted with ethyl acetate and the organic ex~ract is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residual brown oil is purified by chromatography on silica gel with a 95:5 mixture of ethyl acetate and methanol as 30 the eluting agent, whereby there are obtained 128 mg (41%) of t-butyl [(S)-a-[t(S)-l-[[(lS,2R or S)-l-(cyclohexyl-methyl)-2-hydroxy-3-phenyl]carbamoyl]-2-imidazol-4-yl-ethyl]carbamoyl]phenethyl]carbamate as a white solid which melts at 91-93 after recrystalli7ation from ether, MS:
35 632 (M+H) .

2~ 3~

The (2)-a-amino-N-[(lS,2R or S)-l-(cyclohexyl-methyl)-2-hydroxy-3-phenylpropyl]imidazole-4-propionamide dihydrochloride used as the starting material was prepared as follows:

A suspension of 1.45 g (0.06 gram atom) of magnesium shavings in 15 ml of abs. ether is treated dropwise while sticring and passing through argon with a solution of 10.26 g (0.06 mmol) of benzyl bromide in 50 ml of ether in such a manner that the reaction mixture boils slightly under reflux (35 minutes). ~fter completion o~ the addition the reaction mixture is heated to reflux for 3 hours until all of the magnesium shavings have reac~ed.
Thereafter, the reaction mixture is cooled to -60 and treated dropwise within 30 minutes with a solution of 4.82 g (19 mmol) of 2-t-butoxycarbonylamino-3(S)-cyclo-hexylpropylaldehyde [prepared according to the method described by J. Boger et al. in J. Med. Chem., 28, ~779 (1985)]. ThereafteL, the reaction mixture is allowed to warm to room temperature and is poured into ~aturated ammonium chloride solution cooled to 0~. The aqueous phase i5 extracted several times with ether and the combined ether extcacts are washed with saturated ammonium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The oily residue is purified by chromatography on silica gel with a 4:1 mixture o methylene chloride and ethyl acetate-as the eluting agent.
Crystallization from hexane yields Z.295 g (31.5%) of t-butyl [~lS,2R or S)-l-(cyclohexylmethyl)-Z--hydroxy-3~phenylpropyl]carbamate as a white solid, melting point 91~.

500 mg (1.4 mmol) of t-butyl [(lS,2R or S)-l-(cyclo-hexylmethyl)-2-hydroxy-3-phenylpropyl]carbamate are left to stand at room temperature for 2 houcs in 5 ml o 4.6N
hydrochloric acid in methanol. ~hereater, the solvent is 2 ~ 1 3 ~ 7 ~

evaporated under reduced pressure. Crystallization of the residue from hexane yields 369 mg (93%) of (R or S)-a--~(S)-l-amino-2-cyclohexylethyl]-2-phenylethanol hydro-chloride as a white solid, melting point 137-14Z.

In an analogous manner to that described in the first paragcaph o~ this Example, by reacting 1.42 g (5 mmol) o~
(R or S)-a-r(5)-l-amino-2-cyclohexylethyl]-2-phenyl-ethanol hydrochloride with 1-(t-butoxycarbonyl)-N-(t--butoxycarbonyl)-L-histidine there were obtained 2.11 g (72%) o~ t-butyl [~S)-2-[1-(t-butoxyca~bonyl)imidazol-4--yl ] - 1- [ r ( lS,2R or S)-l-(cyclohexylmethyl)-2-hydroxy-3--phenylpropyl]carbamoyl]ethyl]carbamate as colourless crystals, melting point 98-105 (~rom hexane), MS: 585 (MIH) .

1 g (1.7 mmol) of ~-butyl ~(S)-2-rl-(t-butoxy-carbonyl)imidazol-4-yl]-1-rr(lS,2R or S)-l-(cyclohexyl-methyl)-2-hyd~oxy-3-phenylpropyl]carbamoyl]ethyl]carbamate is left to stand at room temperature for 6 hours under argon in 5 ml o~ 4.8N hydrochloric acid in dioxan.
Evaporation o~ the reaction mixture to dryness yields (2)-a-amino-N-[(15,2R or S)-l-(cyclohexylmethyl)-2--hydroxy-3-phenylpropyl]imidazole-4-propionamide dihydro-chloride which is used in the next step without further purification.

xample 2 ln an analogous manner to that described in Example 1, by reacting ~S)-a-amino-N- r (lS,2R or S)-3-cyclohexyl-1--(cylcohexylmethyl)-2-hydroxypropyl]imidazole-4-propion-amide dihydrochloride with ~R)--(pivaloylmethyl)hydro-cinnamic acid (see EPA 0,184,550) there was obtained (S)-N-[(lS,2R or S)-3-cyclohexyl-1-(cyclohexylmethyl)-2--hydroxypropyl]--~(R)-a-(3,3-dimethyl-2-oxobutyl)-2~ '7fjJ

hydrocinnamamido~imidazole-4-propionamide in 40~ yield as a white solid. melting point 164-165 (fcom ethyl acetate/isopropyl ether), MS: 621 (M~H) .

The (S)-a-amino-N-[(lS,2R or S)-3-cyclohexyl-1--~cyclohexylmethyl)-2-hydroxypropyl3imidazole-4-propion-amide dihydrochloride used as the starting material was prepared as follows:

A soluti~n of ~.7 g (13.5 mmol~ o~ t-butyl [(lS,ZR or S)-l-(cyclohexylmethyl)-2-hydroxy-3-phenylpropyl]carbama~e in 100 ml of methanol is hyd~ogenated in the presence of 5 g o rhodium on aluminium oxide (5~ a~ room temperature and under a pressure of 350 kPa. Thereafter, the catalyst is filtered off and the filtrate is evaporated under reduced pressure, whereby there are obtained 4.7 g (98%) of t-butyl [(lS,2R or S)-3-cyclohexyl-1--(cyclohexyl-methyl)-2-hydroxypropyl]carbamate as a white foam which is used in the next step without further puci~ication, MS:
298 (M-isobutylidene) 2Z6 (M-cyclohexylethanol).

A solution of 4.0 g (11 mmol) of t-butyl [(15,2R or S)-3-cyclohexyl-1-(cyclohexylmethyl3-2-hydroxypropyl]-carbamate in 10 ml of ethyl aceta~e and Z0 ml of 2.5N
hydrochloric acid in ethyl acetate is left to stand at room temperature for 2 hours while passing through argon and thereafter the solvent i6 evaporated under reduced pressure. Recrystallization of the crystalline residue obtained from ether/hexane yie~ds 2.42 g (76%) of (2R or S)-3-amino-1,4-dicyclohexyl-2-butanol hydrochloride as colourless crystals, melting point 188-190.

In an analogous mannec to that described in Example 1, by reacting 2 g (7 mmol) o~ (2R or S)-3-amino-1,4-dicyclo-hexyl-2-butanol hydrochloride with l-(t-butoxycacbonyl)-N--(t-butoxycarbonyl)-L-histidine there were obtained 0.80 g (19.4%) of t-butyl 4-r(S)-2-(1-t-butoxyormamido)-Z--[t(lS.2R or S)-3-cyclohexyl-l-(cyclohexylmethyl)-2--hydroxypropyl]carbamoyl]ethyl]imidazole-l-carboxylate as a colourless liquid and 3.0 g (72.6%) of the corresponding diastereomer mixture as a colourless foam. The t-butyl 4-[(S)-2-(1-t-butoxyformamido)-2-t[(lS,2R or S)-3-cyclo-hexyl-l-(cyclohexylmethyl)-2~hydroxypropyl]carbamoyl~-ethyl]imidazole-l-carboxylate was used in t~e next step without furthe~ purification.

In an analogous manner to that described in Example 1, by cleavage of the Boc protecting group there was obtained (S)--a-amino-N-r(lS,2R or S)-3-cyclohexyl-1-(cylcohexyl-methyl)-Z-hydroxypropyl]imidazole-4-propionamide dihydro-chloLide in 73% yield as a white solid, melting point 196-196 (dec., from ethyl acetate).

Example 3 ln an analogous manner to that described in Example 1, by reacting (S)-a-amino-N-r(lS,2R or S)-3-cyclohexyl-1--(cylcohexylmethyl)-2-hydcoxypropyl]imidazole-4-propion-amide hydrochloride with Boc-Phe-OH there wa~ obtained t-butyl r(S)-a-rr(S)-l-[r(lS,2R or S)-3-cyclohexyl-1--(cyclohexylmethyl)-2-hydroxypropyl]carbamoyl]-2-imidazole--4-ylethyl]carbamoyl3phenethyl]carbamate in 49~ yield as a white solid, melting point 183-lB4 (from hexane), MS:
638 (M~-H) .

Exam~_e 4 In an analogous manner to that described in Example 1, by cleaving off the Boc erotecting group from t-butyl [(S)-a-[t(5)-1-tt(lS,2R or S)-3-cyclohexyl-1-(cyclo-hexylmethyl)-2-hydroxyp~opyl]carbamoyl]-2-imidazol-4-yl-ethyl]carbamoyl]phenethyl~carbama~e there was obtained (2R

2 0 ~

or 2S,3S)-1,4-dicyclohexyl-3-(Phe-His-NH)-2-butanol in ~6%
yield as a white solid, melting point 193-195 (dec., from ether), MS: 538 (~H) .

Example 5 In an analogous manner to that described in Example 1, by reacting ~2R or 2S,3S)-1,4-dicyclohexyl-3-(Phe-His-NH)--2-butanol with Boc-D-Pro-OH there was obtained (2R or S,3S)-3-(80c-D-Pro-Phe-His-NH)-1,4-dicyclohexyl-2-butanol in 40~ yield as a white solid, melting point 131-133 (from ethyl acetate/hexane), MS: 735 lM~H) .

ExamPle 6 In an analogous manner to that described in Example 1, by reacting (S)-a-amino-N-[(lS,2R or S)-l-(cyclohexyl-methyl)-2-hydroxyphenethyl]imidazole-4-propionamide with (R)-a-(pivaloylmethyl)hydrocinnamic acid there was obtained (S)-N-[(aS.~R or S)--(cyclohexylmethylj-A--hydroxyphenethyl]-- r (R)-a-(3,3-dimethyl-2-oxobutyl)-hydrocinnamamido]imidazole-4-propionamide in 22% yield as a white solid, melting point 95 (dec., from ethyl acetate/hexane), MS: 601 (M~H) .

The (S)--amino-N-[(lS,2R or S)-l-(cyclohexyl-methyl)-2-hydroxyphenethyl]imidazole-4-propionamide used as the starting material was prepared as follows in an analogous manner to that described in Example 1:

Reaction of 2-t-butoxycarbonylamino-3(S)-cyclohexyl-propylaldehyde with phenylmagnesium bromide in a Grignard reaction yields t-butyl r (aS)-a-(cyclohexylmethyl)-~--hydroxyphenethyl]carbamate in 34% yield as a white solid, melting point 108 (~rom hexane), MS: 260 (M-t-butoxy), 226 (M-benzyl alcohol). Cleavage o~ the Boc protecting group yields a-~(S)-l-amino-2-cyclohexylethyl]benzyl alcohol hydrochlocide in ~7% yield as a white solid, melting point 172 (from hexane). MS: 234 (M+H) , which can be convected by LeactiOn with l-(t-butoxycarbonyl)-N--(t-butoxycarbonyl)-L-histidine in 55% yield into t-butyl ~(S)-2-[1-(t-butoxycarbonyl)imidazol-4-yl]-1-[[(aS,~R or S)-a-(cyclohexylmethyl)-B-hydroxyphenethyl]carbamoyl]-ethyl]carbamate, melting point 97~ (from hexane), MS: 571(M~H) , from which by cleavage of the Boc protecti~g group there is obtained (S)-a-amino-N-r(15,2R or S)-l--(cyclohexylmethyl)-2-hydroxyphenethyl]imidazole-4-propion-amide as an amorphous solid in 74% yield, melting poin~
197-199 (from hexane), MS: 371 (M~H) .
ExamPle 7 In an analogous manner to that described in Example 1, by reacting (S)-a-amino-N-[(2-cyclohexyl-1-(cyclohexyl-methyl)-2-hydroxyethyl]imidazole-4-propionamide hydro-chloride (2:5) with (R)-a-(pivaloylmethyl)hyd~ocinnamic acid there is obtained (S)-N-[(lS,2R or S)-2-cyclohexyl-1--(cyclohexylmethyl)-2-hydroxyethyl]-a[(R)--(3,3--dimethyl--2-oxobutyl)hydrocinnamamido]imidazole-4-propion-amide in 20% yield as a white solid, melting point 97 (from hexane), MS: 607 (M~H) O

The (S)-a-amino-N-[(2-cyclohexyl-1-~cyclohexyl-methyl)-2-hydroxyethyl]imidazole-4-propionamide hydro-chloride used as the starting material was prepared as follows:

Catalytic hydrogenation of t-butyl [(aS)-a-(cyclo-hexylmethyl)-B-hydroxyphenethyl]carbamate in an analogous manner to that described in Example 2 yields t-butyl [(lS,2R or S~-2-cyclohexyl-1-(cyclohexylmethyl)-2-hydroxy-ethyl]carbamate in 93% yield as a colourless foam, MS: Z66 2 ~ 7 ~

(M-t-butoxy), 226 (M-cyclohexylmethanol), which by cleavage of the Boc protecting group with hydrochloric acid in dioxan in an analogous manner to that described in Example 1 yields (lR or S,2S)-2-amino-1,3-dicyclohexyl-1--propanol hydrochloride in 90~ yield as a white solid, melting point 212 (from hexane). Reaction of this compound with l-(t-butoxycarbonyl)-N-(t-butoxycarbonyl)-L--histidine in an analogous manner to that described in Example 1 yields t-butyl [(S)-2 [l-(t-butoxycarbonyl)-imidazol-4-yl]-1-t[(lS,2R or S)-2-cyclohexyl-1-(cyclo-hexylmethyl)ethyl]carbamoyl]ethyl]carbamate in 70% yield as a colourless foam, MS: 577 (M~H) , from which by again cleaving of~ the Boc protecting group there can be prepared (S)-a-amino-N-~(2-cyclohexyl-~-(cyclohexyl-methyl)-2-hydroxyethyl~imidazole-4-propionamide hydro-chloride (2:5) in 72% yield as a white solid, melting point 175 (dec., from hexane), MS: 358 (M-H20).
Example 8 In an analogous manner to that described in Example 1, by reacting (S)-a-amino-N-[(2-cyclohexyl-1-(cyclohexyl-methyl)-2-hydroxyethyljimidazole-4-propionamide hydro-chloride (2:5) with Boc-Phe-OH there was obtained t-butyl [(S~-a- r [ (S)-1-[~2-cyclohexyl-1-(cyclohexylmethyl)-2--hydroxyethyl~carbamoylJ-2-imidazol-4-ylethyl~carbamoyl~-phenethyl]carbamate in 20~ yield as a ~hite solid, melting point 124-127 (from ethyl acetate/hexane), MS: 624 (MIH) .

The (S)-a-amino-N-[(2-cyclohexyl-1-(cyclohexyl-methyl)-2-hydroxyethyl]imidazole-4-propionamide hydro-chloride (2:5) used as the starting material was preparedas follows in an analogous manner to that described in Example 1:

Reaction of Z-t-butoxycarbonylamino-3(S)-cyclohexyl-propylaldehyde with cyclohexylmagnesium bromide in a Grignard reaction yields in 59~ yield t-butyl ~(2-cyclo-hexyl-l-(cyclohexylmethyl)-2-hydroxyethyl]carbamate as a mixture of diastereomers in the form of a colourless oil, MS: 284 (M-isobutylidene), 226 (~-cyclohexylmethanol), which, after cleavage of the Boc protecting group with hydrochloric acid in dioxan, yields a mixture of diastereomers of 2-amino-1,3-dicyclohexyl-1-propanol hydrochloride in 57% yield, melting point 191-198 (from hexane) MS: 240 (M~H) , 156 (M-cyclohexane), 126 (M-cyclohexylmethanol). By reaction with l-(t-butoxy-carbonyl)-N-(t-butoxycarbonyl)-L-histidine there i5 obtained in 48% yield t-butyl r ( s ) - 1- [ 1- ( t-butoxy-carbonyl)imidazol-4-yl]-1-r[2-cyclohexyl-1-(cyclohexyl-methyl)ethyl]carbamoyl]eth~l]carbamate as a white foam, MS: 577 (M~H) . Cleavage of the Boc protecting group ~rom the just-named compound yields (S)-a-amino-N-[(2--cyclohexyl-l-(cyclohexylmethyl)-2-hydroxyethyl]imidazole--4-propionamide hydrochloride (2:5) in 72~ yield as a white solid, melting point 175 (dec., from hexane), MS:
377 (M~H) .

Example__9 740 mg (1 mmol) of (S)-N-r(lS,2S)-l-(cyclohexyl-methyl)-4-et-hyl-4-fluoro-2-hydroxyhexyl]--[(R)-a--(3,3 dimethyl-2-oxobutyl)hydrocinnamamido]-1-(t-butoxy-carbonyl)imidazole-4-propionamide are dissolved in 10 ml of methanol, treated with 10 mg of potassium carbonate and stirred at room temperature for 1.5 hours. Thereafter, the reaction mixture is evaporated and the residue is chromatographed on 50 g of silica gel with a 1000:50:1 mixture o~ chloroiorm, ethanol and ammonia as ~e eluting agent, whereby thece are obtained 57 mg (9~) of (R)-N--[(15,2S)-l-(cyclohexylmethyl)-4-ethyl-4-fluoro-~-hydroxy-2 ~ 7 ~

hexyl]-a-r(R)-a-(3,3-dimethyl-2-oxobutyl)hydrocinnam-amido~imidazole-4-propionamide as an oil and 317 mg (50%) of the epimeric compound (S)-N-[(lS,2S)-l-(cyclohexyl-methyl)-4-ethyl-4-fluoro-2-hydroxyhexyl]-a-r(R)-a--(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4--propionamide as a foam, MS (both): 627 (M+H) .

The (S)-N- r (lS,2S)-l-(cyclohexylmethyl)-4-ethyl-4--fluoro-2-hydroxyhexyl]-~-[(R)-a-~3,3-dimethyl-2-oxo-butyl)hydrocinnamamido]-l-(t-butoxycarbonyl)imidazole-4--propionamide used as the starting material was erepared as follows:

0.95 g (2.9 mmol) of t-butyl [(lS,2S)-l-(cyclohexyl-methyl)-2-hydroxy-3-(methoxycarbonyl)propyl]carbamate, prepared according to the method described in EPA 0,165,226, in 20 ml of dimethoxypropane and 50 mg (0.2 mmol) of p-toluenesulphonic acid are stirred at room temperature for Z4 hours. Subsequently, the reaction mixture is extracted three times with 150 ml of ether each time and the ether extracts are washed with sodium bicarbonate solution and saturated sodium chloride solution. After drying and evaporating the ether extracts the residue is chromatographed on 80 g o~ silica gel with a 9:1 mixture o~ toluene and ethyl acetate as the eluting agent, whereby there are obtained 900 mg (84%) of t-bu~yl (4S,5S)-l-(cyclohexylmethyl)-5- r (methoxycarbonyl)methyl]--2,2-dimethyl-3-oxazolidinecarboxylate, MS: 370 (M+H) .

850 mg (2.3 mmol) of t-butyl (4S,5S)-l-(cyclohe~yl-methyl)-5-t(methoxycarbonyl)methyl]-2,2-dimethyl-3--oxazolidinecarboxylate in 15 ml of te~rahydrofuran are added dropwise at room temperature to a Grignard solution prepared ~rom 55~ mg (23 mgram atom) of magnesium sha~ings and 1.72 ml (23 mmol) oi ethyl bromide in 15 ml of tetra-hydrofuran. The reaction mixture is subsequently stirred 2 ~

at room tempecature for a further 1.5 hours, then poured into a mixture of ice and ammonium chloride solution and extracted three times with 150 ml of ether each time. The ether extracts are washed with 70 ml of water, combined, dried and evaporated. Chromatography of the residual oil (6B0 mg) are chromatographed on 30 g of silica gel with a 95 5 mixture of toluene and ethyl acetate containing 1%
triethylamine as the eluting agent, whereby there are obtained 600 mg (66~) of t-butyl (4S,5S)-4-(cyclohexyl-methyl)-5-(2-hydroxy-2-ethylbutyl)-2,2-dimethyl-5--oxazolidinecarboxylate as an oil, MS: 398 (M~H) .

A solution of 5~0 mg (1.45 mmol) of t-butyl (4S,5S)-4--(cyclohexylmethyl)-5-(2-hydroxy-2-ethylbutyl)-Z,2--dimethyl-5-oxa~olidinecarboxylate in 2 ml of methylene chloride is added dropwise at -78 under argon to a solution of 0.53 ml (4.38 mmol) o~ diethylaminosulphur trifluoride in 1 ml o methylene chloride and the reaction mixture is subsequently stirred at this temperature for 5 hours. Thereafter, the reaction mixture is partitioned between methylene chloride and water and the organic phase is washed once with water, dried over magnesium sulphate and evaporated. The residue (560 mg of oil) is chromato-graphed on 70 g of silica gel with a 98:z mixture of toluene and ethyl acetate as the eluting agent, whereby there are obtained 500 mg of an oil which is used directly in the next step.

500 mg of the above oil are stirred for 45 minutes at room tempera~ure under argon in a solution of 2.5 ml of 4M
chlorotrimethylsilane in methylene chloride and 7.5 ml of 4M phenol in methylene chloride. Thereafter, the reaction mixture is poured on to ice and extracted twice with 150 ml of methylene chloride. The organic extracts are washed with 70 ml of water and 70 ml o~ saturated sodium chloride &olution, combined, dried over magnesium sulphate, filtered and evaporated. Chromatography of the residual oil (1.66 g~ on 70 g of silica gel with a 20:~:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent yields 177 mg of (aS,~S)-B--amino-a-(2-ethyl-2-fluorobutyl)cyclohexylpropanol as a white solid, MS: 260 (M~H) .

167 mg (0.64 mmol) of (aS,~S)-B-amino-a-(2-ethyl--2-fluorobutyl)cyclohexylpropanol and 345 mg (0.71 mmol) of l-(t-butoxycarbonyl)-N-r(R)-a-(3,3-dimethyl-2-oxo--butyl)-hydrocinnamoyl]-L-histidine in 10 ml oi dime~hyl-formamide a~e treated in succession with 0.1 ml (0.71 mmol) of triethylamine, 116 mq (0.71 mmol) of HOBT
and 289 mg (0.71 mmol) of HBTU and the reaction mixture is stirred at oom temperatuce for 3 hours. Thereafter, it is poured on to ice and 70 ml of 2N sodium bicarbonate solu~ion and extracted three times with 150 ml of ethyl acetate each time. The organic extracts are washed once with ice and 70 ml of saturated ammonium chloride solution and once each time with 70 ml of 2~ sodium bicarbonate solution and 70 ml of saturated sodium chloride solution, dried over magnesium sulphate, filtered and evapocated, whereby there are obtained 740 mg of crude (S)-N-[~lS,2S)--l-(cyclohexylmethyl)-4-ethyl-4-fluoro-2-hydroxyhexyl]-a--[(R)-a-(3,3-dimethyl-~-oxobutyl)hydrocinnamamido]-1--(t~butoxycarbonyl)imidazole-4-propionamide which i6 used directly in the next step without further purification.

The l-(t-butoxycarbonyl)-N- r (R)-a- (3, 3-dime~hyl-2--oxobutyl~-hydrocinnamoyl~-L-histidine which is also used as a starting material was prepared as follows:

A suspension of 3.~ g (12 mmol) of (R)-a-(pivaloyl-methyl)hydrocinnamic acid and 2.66 g (11 mmol) of L-histidine methyl ester dihydcochloride in 340 ml of dimethylformamide is treated at room temperature under a ~ J, nitrogen atmosphere with 3.45 g (34 mmol) of triethylamine and 4.58 g (12 mmol) of HBTU. The reaction mixture is stirred at room temperature for 5 hours and subsequently evaporated in a high vacuum. The residue is dissolved in 500 ml of ethyl acetate and washed in succession with 100 ml of water, three times with 100 ml of saturated sodium bicarbonate olution each time and with 100 ml of saturated sodium chloride solution. The organic phase is dried oveL sodium sulphate, evaporated under reduced pressure and the yellowish crude product obtained is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol containing 0.1% ammonia.
In this manner there are obtained 3.6 g of N-r(R)-a--(3,3-dimethyl-2-oxobutyl)hydrocinnamoyl]-L-histidine methyl ester as a coloucless foam, MS: ~99 (M) .

A solution of 3.56 g (8.9 mmol) of N-[(R)-a-(3,3--dimethyl-2-oxobutyl)hydrocinnamoyl~-L-histidine methyl ester and 9.36 ml of lN sodium hydroxide solution in 50 ml of methanol is stirred at room temperature for 15 hours and thereafter evaporated under reduced pressure in the cold. The residue is dissolved in 70 ml of dioxan and 25 30 ml o~ water, a solution of 2.95 (13.5 mmol~ of di-t--butyl dicarbonate is added dropwise the~eto at room temperature and the mixture is thereafter sti~red at room temperature for 15 hours. For the working-up, the reaction solution is concentrated to about 1/3 of its volume under reduced pressure and then diluted with 200 ml of ethyl acetate. After the addition of 50 ml of ice-water the reaction mixtule is adjusted to pH 2.5 and the aqueous phase is saturated with solid sodium chloride. The aqueous phase is extracted twice with ethyl acetate and the combined ethyl acetate phases are dried over ~odium sulphate and evaporated. The crude product obtained is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol containing 0.1% acetic 2a~3~

acid, whereby there are obtained 3.5 g of l-t~-butoxy-carbonyl)-N-[(R)-a-(3,3-dimethyl-2-oxobutyl)-hydro-cinnamoyl]-L-histidine as a colourless powder, MS: 486 (MIH) , Exam~le 10 200 mg (0.3 mmol) of benzyl ~(S or R)-1-r(S)-2-cyclo-hexyl-l-~(S)-a-r(R)-a-(3,3-dimethyl-2-oxobutyl)hydro-cinnamamido]imidazol-4-propionamido]ethyl]-2-ethylbutyl]-carbamate are hydrogenated for 8 hours at room temperature and atmosphe~ic p~essure in the presence of 10 mg of 10 palladium on charcoal in 30 ml of methanol. ~ter completion of the hydrogen uptake the catalyst is filtered off and the filtrat,e i5 evaporated under reduced pressure, whereby there are obtained 163 mg (100%) o~ (S)-N-[(lS,2S
or R)-2-amino-1-(cyclohexylmethyl)-3-ethylpentyl]-a--[(R)--(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-imidazole-4-propionamide in the form of a solid, MS: 594 (M~H) .

In an analogous manner to that described above, by catalytically hydrogenating 50 mg o4 benzyl [(R or S)-l--[(S)-Z-cyclohexyl-l- r (s)-- r (R)-a-(3,3-dimethyl-2-oxo-butyl)hydrocinnamamido]imidazol-4-propionamido]ethyl]-2--ethylbutyl]carbamate in the presence of 5 mg of 10~
palladium on charcoal in 1~ ml of methanol there are obtained 40 mg (98%) of (S)-N-r(lS,2R or 2S)-2-amino-1--(cyclohexylmethyl)-3-ethylpentyl]-a-r(R)-a-(3,3--dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-proeion-amide as a foam, MS: 594 (M~H) .

The benzyl r(S oc R)-l-[(S)-2-cyclohexyl-1-r(S)-a--[(R)-a-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-imidazol-4-propionamido]ethyl]-2-ethylbutyl]carbamate and benzyl [(R or S)-l-[(S)-2-cyclohexyl-1-(S)-a-[(R)-a-2~3~i - 4a --(3,3-dimethyl-2-oxobutyl)hydr~cinnamamido]imidazole-4--propionamido]ethyl]-2-ethylbutyl]carbamate used as the stacting materials were prepared as follows:

2.28 g (8 mmol) of t-butyl [(S)-l-(cyclohexylmethyl)--l-(methoxycarbonyl)methyl]cacbamate ~see J. Bogec et al., J. Med. Chem. 28, 1779 (1985~] in 30 ml of tetrahydrofuran are added dropwise at room temperature to a Grignard solution prepared from 0.61 g ~25 mgram atom) of magnesium shavings and 3.12 ml (25 mmol) of 3-bromopentane in 35 ml of tetrahydrouran and the rea~tion mixture is stirred at room temperature overnight. Su~sequently, the mixture is treated dropwise with abou~ 40 ml of saturated ammonium chloride solution while cooling in an ice bath and extracted three times with 300 ml of ather each time. The o~ganic extracts are washed with 100 ml of water and lO0 ml of saturated sodium chloride solution, combined, dried and evaporated. Chromatogcaphy of the residue (2.95 g) on 250 g of silica gel with a 9:1 mixture of hexane and ether as the eluting agent yields 670 mg (26%) of t-butyl [(S)-l-(cyclohexylmethyl)-3-ethyl-2-oxopentyl]-carbamate as a yellow oil, MS: 336 (M~-H) .

A mlxture of 550 mg (1.66 mmol~ 4f t-butyl r(S)-l--(cyclohexylme~hyl)-3-ethyl-2-oxopentyl]carbamate, 3 ml of pyridine, 1.15 g (1.66 mmol) of hydroxylamine hydro-chloride and l.01 g of 4-dimethylaminopyridine is heated 3 to 100 for 5 hours undec argon. Thereafter, the reaction mixture is evaporated to dryne~s in a high vacuum and the residue is extracted three ti~es with 130 ml of ether each time. The organic extcacts are washed in succession with 70 ml of 2N sodium bica~bonate solution, 20% copper sulphate solution and water, dried and evaporated under reduced pressure. The residue remaining (540 mg) in lO0 ml of 3.5N methanolic ammonia is stirred under a hydrogen atmosphere for 2 days in the presence of l g of Raney-~3~

-nickel. Thereafter, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. Chromato-graphy of the cesidue on 50 g of silica gel using a 95:5mixture of chloroform and ethanol as the eluting agent yields 260 mg (48~) of t-butyl r(lS,2RS)-2-amino-1-(cyclo-hexylmethyl)-3-ethylpentyl]carbama~e as an oil, MS: 327 (M~H) ~ mixture of 260 mg ~0.8 mmol) of t-butyl [(lS,2RS)-2--amino-l-(cyclohexylmethyl)-3-ethylpentyl]carbamate, 0.22 ml (1.60 mmol) of triethylamine, 240 mg ~0.9~ mmol) of N-(benzyloxycarbonyloxy)succinimide and 15 ml of methylene chloride is stirred at room temperature for 2 hours. Thereafter, the reaction mixture is evaporated under reduced pressure and the residue is poured on to ice and extracted twice with 150 ml of ether each time. The organic ex~racts are washed with 2N sodium carbonate solution and water, combined, dried and evaporated.
Chromatography of the residue on 50 g of silica gel with a 97:3 mixture of toluene and ethyl acetate as the eluting agent yields the two epimeric compounds 2-benzyl l-t-butyl r(lS,2S or R)-l-(cyclohexylmethyl)-2-(1-ethylpropyl)-ethylene]dicarbamate (2~0 mg) and 2-benzyl l-t-butyl ~(lS,2R or S)-l-(cyclohexylmethyl)-2-(1-ethylpropyl)-ethylene]dica~bamate (80 mg), both as an oil, MS (both):
461 (M~H) .

In an analogous manner to that described in Example 9, by reacting 2-benzyl l-t-butyl r(lS,2S or R)-l-(cyclo-hexylmethyl)-2-tl-ethylpropyl)ethylene]dicarbamate and Z-benzyl l-t-butyl [~lS,2R or S)-l-(cyclohexylmethyl)-2--(l-ethylpropyl)ethylene]dicarbamate with l-(t-butoxy-carbonyl)-N-[(R)-a-(3,3-dimethyl-2-oxobutyl)hydro-cinnamoyl~-L-histidine and subsequently cleaving off the Boc protecting group in the imidazole ring with potassium carbonate in methanol there are obtained the two epimeric 2 ~

compounds benzyl [(S or R)-l-[(S)--2-cyclohexyl-1-t(S)-a--r(R~-a-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido~-imidazol-4-propionamido]ethyl]-2-ethylbutyl]carbamate and benzyl t(R or S)-l-[(S)-2-cyclohexyl-1-r(S)-a-t(R)-a--(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4--propionamido]ethyl]-2-ethylbutyl]carbamate, both as a foam, MS (both): 728 (MtH) .

Example 11 In an analogous manner to that described her.einafter for the preparation of the starting material, 750 mg (1.19 mmol) of (S)-~-amino-N-t(lS,ZRS)-l-(cyclohexyl-methyl)-2-hydroxy-4,4-dimethylpentyl]imidazole-4-propion-amide and 337 mg (1.36 mmol) of (R)-a-(pivaloylmethyl)-hydrocinnamic acid were reacted with one another in 20 ml of dimethylfocmamide and the reaction mixture was worked--up. Chromatography of the residue on 65 g of silica gel with a 200:1~:1 mixture of methylene chloride, methanol and ammonia yields 420 mg (59%) of (S)-N-t(lS,2RS)-l--(cyclohexylmethyl)-2-hydroxy-4,4-dimethylpentyl]-a--[(R)-a-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]-imidazole-4-propionamide as an amorphous powder, MS: 595 (M~H) .

The (S)-a-amino-N- r (lS,2RS)-l-(cyclohexylmethyl)-2--hydroxy-4,4-dimethylpentyl]imidazole-4-propionamide used as the starting material was prepared as follows:

1.64 g (67 mgram atom) of magnesium shavings in ether are treated dropwise with 8.85 ml (70 mmol) of l-bromo--2,2-dimethylpropane in 80 ml of ether in such a manner that the reaction mixture boils slightly under reflux.
After completion of the addition the reaction mixture is cooled to -60 and treated within 30 minutes with a solution of 5.1 g (20 mmol) of 2-t-butoxycarbonylamino-2~3.~

- 5~ --3(S)-cyclohexylpropylaldehyde in 60 ml of ether.
Subsequently, the reaction mixture is stirred at coom temperature overnight, then cooled to 5 in an ice bath and treated dropwise with 25 ml of saturated ammonium chloride solution. The reaction mixture i8 thereafter extracted three times with 300 ml of ether and the ether extracts are washed with saturated ammonium chloride solution and water. The oil (6.62 g) remaining after drying and evaporation is chromatographed on 500 g of silica gel with firstly a 98:2 and subsequently a 95:5 mixture of methylene chloride and ethyl acetate as the eluting agent, whereby there are obtained 4.11 g (63~) of t-butyl [(lS,2RS)-l-(cyclohexylmethyl)-2-hydroxy-4,4--dimethylpentyl]carbamate as an oil, MS: 32~ (M~H) .

4.Ll g (12.5 mmol) of t-butyl [(lS,2RS)-l-(cyclohexyl-methyl)-2-hydroxy-4,4-dimethylpentyl]carbamate are left to stand at room temperature for 4 hours in 1.58M hydro-chloric acid in dioxan. Thereafter, the reaction mixture is evaporated to dryness under reduced pressure, whereby there are obtained 1.24 g (38%) of (aRs,~S)-B-amino-a--(2,2-dimethylpropyl)cyclohexylpropanol hydrochloride which is u~ed in the next step without further purifica-tion.

A mixture of 1.24 g (4.7 mmol) of (aRs,~S)-~-amino--a-(2,2-dimethylpropyl)cyclohexylpropanol hyd~ochloride, 3.24 g (5.4 mmol) o (Fmoc)2His-OH, 1.78 ml (14.1 mmol) - of 4-ethylmorpholine, 1.6B g (10.8 mmol) of 87% HOBT, 1.244 g (6.49 mmol) of EDC and 50 ml of dimethylformamide is left to stand a~ room temperature overnight. The reaction mixture is thereafter concentrated at below 40 in a high vacuum and extracted three times with 5DO ml of ethyl acetate. The organic extracts are washed in succession with 120 ml of 2N sodium bicarbonate solution, lZO ml of saturated ammonium chloride solution, 120 2N

sodium bicarbonate solution and 120 ml of saturated sodium chloride solution. The residue (4.7 g) remaining after drying and evaporation is dissolved in 100 ml of methylene chloride and filtered. The filtrate is treated with 2 ml of pyridine and stirred at room temperature for 2 hours.
Thereafter, the reaction mixture is evaporated and the residue is chromatographed on silica gel, whereby there are obtained 750 mg (44%) of (S)-a-amino-N-[(lS,2RS)-l--(cyclohexylmethyl)-2-hydroxy-4,4-dimethylpentyl]imidazole--4-propionamide as a thin-layer chromatographically uniform p~oduct and are used directly in the next step.

ExamDle I2 In an analogous manner to that described in Example 11, by reacting (S)-a-amino-N-[(lS,2RS)-l--(cyclohexylmethyl)-2-hydroxy-3,3-dimethylbutyl]imidazole--4-propionamide with (R)-a-(pivaloylmethyl)hydrocinnamic acid there was obtained N-r(lS,2RS)-l-(cyclohexylmethyl)--2-hydroxy-3,3-dimethylbutyl]-a- r (K)-a- (3,3-dimethyl--2-oxobutyl)hydrocinnamamido]imidazole-4-pLopionamide as a foam, MS: 581 (M~H) .

ln an analogous manner, by reaction with N-isobutoxy-carbonyl-L-phsnylalanine in place of (R)-a- ~pivaloyl-methyl)hydrocinnamic acid there was obtained isobutyl [(S)--[[(S)-l-[[(lS,2RS)-l-(cyclohexylmethyl)-2--hydroxy-3,3-dimethylbutyl]carbamoyl]-2-imidazol-4-yl-ethyl]carbamoyl~phenethyl]carbamate a~ a foam, MS: S98 (M~H) .

The (S)-a-amino-N-[(lS,2RS)-l-(cyclohexylme~hyl)-2--hydroxy-3,3-di~ethylbutyl]imidazole-4-propionamide used as the starting material was prepared as ~ollows in analogy to Example 11:

.
Reaction of 2-t-butoxycarbonylamino-3(S)-cyclohexyl-propylaldehyde with t-butyllithium in hexane in place of the reaction with a corcesponding Grignard compound yields t-butyl t(lS,2RS)-l-(cyclohexylmethyl)-2-hydroXy-3,3--dimethylbutyl]carbamate as an oil, MS: 314 (M+H) , which by cleavage of the Boc protecting group with hydro-chloric acid in dioxan can be converted into (aRS,~S)-B--amino-a-(2,2-dimethylethyl)cyclophexylpropanol hydro-chloride, MS: 214 (M+H) . Reaction of this compound with (Fmoc)2His-OH and cleavage of the ~moc protecting groups with piperidine yields (S)-a-amino-N-r(lS,2RS)-l-(cyclo-hexylmethyl)-2-hydroxy-3,3-dimethylbutyl]imidazole-4-15- -propionamide which is used in the next s~ep withou~
further purification.

Example 13 In an analogous manner to that described in Example 11, by reacting (S)-~-t(S)-l-amino-2-cyclohexyl-ethyl]-2-benzimidazolehexanol with l-(t-butoxycarbonyl)-N--~(R)--(3,3-dime~hyl-2-oxobutyl)hydrocinnamoyl]-L--histidine and cleaving off the Boc protecting group with potassium carbonate in methanol there was obtained (S)-N--[(15,2S)-7-(2-benzimidaæolyl)-1-(cyclohexylmethyl)-Z--hydroxyheptyl]-a-r(R)-a-(3,3-dimethyl-2-oxobutyl)-hydrocinnamamido]imidazole-4-propionamide in the form of a beige coloured amorphous solid, MS: 711 (M+~) .
The (S)-~-[(S)-l-amino-2-cyclohexyle~hyl]-2-benz-imidazolehexanol used as the starting material was prepared as follows:

A solu~ion of 40.7 ml (0.3 mol) of 6-bromo-1-hexene in 270 ml of ether is added dropwise within 75 minutes under argon to 7.4 g ~0.3 gram atom) of magnesium shavîngs in 60 ml o~ ether in such a manner that the reaction mixture ~0:~3/~ ~

boils slightly. After completion of the addition the reaction mixture is heated to rèflux fo~ a further 45 minutes, thereaEter cooled to -60~ and treated within 1 hour with 20 g (0.080 mol) of 2-t-butoxycarbonylamino--3tS)-cYclohexylpropylaldehyde in 270 ml of ether at -60 to -70. ~fter completion of the addition the reaction mixture is stirred for 18 hours without cooling, there-after again cooled to 5 and t~eated with 400 ml ofsaturated ammonium chloride solution. The two phases are separated and the organic phase is dried over magnesium sulphate and evaporated. The residue is chromatographed on 4Z0 g of silica gel with methylene chloride and increasing amounts of ethyl acetate as the eluting agent, whereby there are obtained 19.3 g (71~) of t-butyl r(lS,2S:R=4~
-l-(cyclohexylmethyl)-2-hydroxy-7-octenyl]carbamate as an oil, MS: 284 (M-C4H7)-18.5 g (54.5 mmol) of t-butyl ~(lS,2S:R=4:1)-1-(cyclo-hexylmethyl)-2-hydroxy-7--octenyl]carbamate are dissolved in 133 ml o~ 2,2-dimethoxypropane and treated with 2.55 g (13 mmol) of p-toluenesulphonic acid monohydrate. There-after, the reaction mixture is stirred at room temperature for 4 hour~, subsequently poured into a mixture of ice--water and sodium bicarbonate solu~ion and extracted with ethyl acetate. The organic ~xtracts are dried over magnesium sulphate and evaporated, whereby there are obtained 20.2 g of a yellow oil which is chromatographed 30 on 200 g of silica gel with a 9:1 ~ixture of methylene chloride and hexane as the eluting agen~. There are thus obtained 19.0 g ~92%) of t-butyl (4S,5S:R=4:1]-4-(cyclo-hexylmethyl)-5-(5-hexenyl)-2,2-dime~hyl-3-oxazolidine-carboxylate as a yellowish oil, MS: 3h4 (M-CH3).

2.5 ml (25 mmol) of borane-dimethyl sulphite complex are added dropwise within 5 minutes to 19.0 g (50.1 mmol) of t-butyl (4S,5S:R=4:1]-4-(cyclohexylmethyl~-5-(5-~a~3~

-hexenyl)-Z,2-dimethyl-3-oxazolidinecarboxylate in 100 ml of hexane. Thereafter, the reaction mixture is stirred at 0 for 10 minutes and subsequently a~ room temperature for 3.5 hours. Thereafter, it is again cooled and there are added dropwise thereto firstly at 0-50 within 10 minutes 16.8 ml of ethanol and subsequently again within 10 minutes 8.5 ml of 2N sodium hydroxide solution. ~fter stirring at 5 for 5 minutes 12.7 ml of 30% hydrogen peroxide solution are added dropwise within 20 minutes at a maximum temperature of 8. Thereafter, the reaction mixture is heated to reflux for 2 hours, cooled, poured into 500 ml of water and extracted with methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and evapora~ed, and the residue is chromatog~aphed on 240 g of silica gel, whereby there is used as the eluting agent firstly a 98:2 mixture and then a 95:5 mixture of methylene chloride and isopropanol. ln this manner ~here are obtained 12.8 g (64%) of t-butyl (4S,5S)-4-(cyclohexylmethyl)-5-(6-hydroxyhexyl~-2,Z--dimethyl-3-oxazolidinecarboxylate as a mixture of isomers. By crystallization from ether/hexane there are obtained 7.2 g (36%) of t-butyl (4S.5S)-4-(cyclohexyl-methyl)-5-(6-hydroxyhexyl)-2,2-dimethyl-3-oxazolidine-carboxylate as a pure isomeric compound, melting point 64 (~rom diethyl ether/hexane).

4.0 g (10.1 mmol) of t-bu~yl (4S,5S)-4-(cyclohexyl-methyl)-5-(6-hydroxyhexyl)-2,2-dimethyl-3-oxazolidine-carboxylate 2re dissolved in 60 ml of benzene and thereafter treated with 7.95 g (50 mmol) of powdered potassium permanganate, 34 ml of water and 1.4 g of tricaprylmethylammonium chloride in 10 ml o benzene.
Thereafter, the reaction mixture is cooled to 5 and treated with 6.7 ml of glacial acetic acid. Then, the reaction mixture is stirred intensively at room temperature for 3 hours, subsequently poured into 400 ml 2 0 ~

of ice-water, decolorized by the addition of sodium pyrosulphite and extracted with methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and evaporated. The residue obtained is chromato-graphed on 60 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent, whereby there are obtained 3.4 g (82%) of (4S,5S)-3-(t-butoxy-cacbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidine-hexanoic acid as a colourle~s, crystallizing oil which is used directly in the next step.

1.2 g (2.9 mmol) of (4S,5S)-3-(t-butoxycarbonyl)-4--(cyclohexylmethyl)-2,2-dimethyl-5-oxazolidinehexanoic 1 acid are dissolved in 5 ml of tetrahydrofuran and treated with 0.44 ml (3.1 mmol) of triethylamine. Therea~ter, the reaction mixture is cooled tn -20 and treated within 5 minutes with a solution of 0.42 ml (0.31 mmol) of isobutyl chloroformate in 1 ml of tetrahydrofuran. After stirring at -20 ~or 1 hour a solution of 0.63 g (5.8 mmol) of 1,2-phenylenediamine in 5 ml of tetrahydro-furan is added dropwise at -20 within 5 minutes. There-after, the reaction mixture is stirred at -20 for 30 minutes and then at room temperature for 3.5 hours.
Then, the reaction mixture is poured into ice-water and ~xtracted with methylene chloride, and the methylene chloride extracts are dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on Z0 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent, whereby there are obtained 1.4 g (96%) of t-butyl (4S,5S)-5-(5-[(o-amino-phenyl)carbamoyl]pentyl]-4-(cyclohexylmethyl)-2,2-dimethyl--3-oxazolidinecarboxylate as an oil, MS: 501 (M~H) .

1.4 g (2.79 mmol) of t-butyl (4S,5S)-5-(5-[(o-amino-phenyl)carbamoyl]pentyl]-4-(cyclohexylmethyl)-2,2-dimethyl--3-oxazolidinecarboxylate are dissolved in 25 ml of 2 ~

methanol, cooled to 0 and treated with 8.5 ml of 3.88M
hydrochloric acid in methanol. Subsequently, the reaction mixture is stirred at room temperature for 24 hours. It is then poured into ice-water, made alkaline with lN sodium hydroxide solution and extracted three times with a 4:1 mixture of methylene chloride and isopropanol. The organic extracts are dcied over magnesium sulphate and evaporated.
and the re5idue is heated to reflux for 1 hour in a mixture of 15 ml of methanol and 1.5 ml of conc. aqueous hydrochloric acid. The reaction mixture is then again worked-up as described above and the crude product obtained is heated to reflux or 2 hours in 20 ml of aqueous 3N hydrochloric acid. The 760 mg of crude product obtained after a third working-up as described above are chromatographed on 8 g of silica gel with methylene chloride and increasing amounts of isopropanol and aqueous concentrated ammonia as the eluting agen~, whereby there are obtained 346 mg (36%) of (S)-~-[(S)-l-amino-2-cyclo-hexylethyl]-2-benzimidazolehexanol as an oil, MS: 344 (M~H) ExamPle 14 0.35 g (1.33 mmol) of Boc-Phe-OEl, 0.28 g of EDC and O.Zl g of HOBT are dissolved in 7.5 ml of methylene chloride and trea~ed at -10 wi~h a solution of 0.50 g (1.33 mmol) of (S)-a~amino-N-r(lS,2S,4R)-l-(cyclohexyl-methyl)-4-ethyl-Z-hydroxy-5-hexenyl]imidazole-4-propion-amide in 7.5 ml of methylene chloride. Thereafter, ~he reaction mixture is stirred at -10 for 2 hours and subsequently at room temperature for 18 hours. For the working-up, the reaction solution is poured into 2N sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extracts are dried over potassium carbonate and evaporated, and the residue is chromatographed on 10 g of silica gel with methylene chloride and increasing amounts o~ isopropanol as the eluting agent. In this manner there is obtained 0.73 g (88~) of t-butyl t(S)-a-[r(S)-l-[[(lS,ZS,4R)-l-cyclo-hexylmethyl)-2-hydroxy-4-ethyl-5-hexenyl]carbamoyl]-z--imidazol-4-ylethylcarbamoyl]phenethyl]carbamate as an amorphous white solid, MS: 624 (M+H) .

ln an analogous manner to that described above, by reacting (S~-a-amino-N-r~lS,2S,4S)-l-cyclohexylmethyl)--4-ethyl-2-hydroxy-5-hexenyl~imidazole-4-propionamide ~here is obtained t-butyl r (s)-- [ [ (S)-l- r [ (lS,2S,4S)-l--~cyclohexylmethyl)-2-hydroxy-4-ethyl-5-hexenyl]carbamoyl]--2 imidazol-4-ylethyl]cacbamoyl]-Z-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamate as an amorphous white solid, MS: 624 (M~H) .

The (S)-a-amino-N-~(lS,2S,~R)-l-(cyclohexylmethyl)--4-ethyl-2-hydroxy-5-hexenyl]imidazole-4-propionamide and (S)-a-amino-N- r (lS,2S,4S)-l-cyclohexylmethyl)-2-hydroxy--4-ethyl-5-hexenyl]imidazole-4-propionamide used as the starting materials were prepared as follows:

A solution of 44.9 g (0.276 mmol) o~ 3-(bromomethyl)--l-pentene, prepared according to the method described by C. Jennings-White and R. G. Almquist in Tetrahedron Letters, 2533 (198Z), in 225 ml of ether is added dropwise within 90 minutes to 6.72 g (0.28 gram atom) of magnesium shavings in 75 ml of ether under argon in fiuch a manner ~hat the reaction mixture boils slightly. After completion of the addition the reaction mixture is heated ~o reflux for 3.5 hours, then cooled to -60 and ~reated dropwise within 50 minutes with a solution of 22.6 g (0.075 mol) of 2-~-butoxycarbonylamino-3(S)-cyclohexylpropylaldehyde in 2Z5 ml of ether. whereby ~he temperature amounts to -60 to -70. After completion of the additisn the cooling bath is removed and the reaction mixture is stirred at room 20~ 3~7~

te~perature for 18 hours. Then, it is cooled to 5 and there are added thereto while stirring 100 ml of a saturated ammonium chloride solution, whereby the temperature rises to 20. The two phases are separated, the organic phase is dried over magnesium sulphate and concentrated, and the residue is chromatographed on 1 kg of silica gel with methylene chloride containing 0 to 20%
ethyl acetate as the eluting agent. There are thus obtained 9.8 g (38.5~) of (aS,~S)-B-t-butoxycarbonyl-amino-a- r (R)-2-ethyl-3-butenyl]-cyclohexylpropanol, 2.7 g (11%3 of (aS,~S)-t-butoxycarbonylamino-a-t(S)-2--ethyl-3-butenyl]cyclohexyl~ropanol as well as 10.0 g (39%) of a ~ixture of the two named diastereomers in the ~orm of oils which are used in the next step without further purification.

3.5 g (10.3 mmol) of (aS,~S)-~-t-butoxycarbonyl-amino-a-[(R)-2-ethyl-3-butenyl]cyclohexylpropanol are stirred at room temperature for 90 minutes in a mixture of 25 ml of methylene chloride and 15 ml o~ gO% trifluoro-acetic acid. Therea~ter, the reaction mixture is poured into water, made alkaline and ex~racted with methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and evaporated, and the cesidue is chromatographed on 2~ g of silica gel with an 80:20:1 mixture of methylene chloride, isopropanol and ammonia as the eluting agent, whereby there are obtained 2.2 g (89%) of (2S,3S,5R)-2-amino-5-ethyl-1-cyclohexyl-6-hepten-3-ol as a colourless oil, MS: 14Z (M-C7H13).

In an analogous manner, by reacting (nS,~S~-B-t--butoxycarbonylamino-a-r(S)-2-ethyl-3-butenyl]cyclohexyl-propanol with trifluoroacetic acid there is obtained (2S,3S,5S)-2-amino-5-ethyl-1-cyclohexyl-6-hepten-3-ol as a yellowish solid, MS: 240 (M~H) .

2~3~

2.2 g (9.19 mmol) o~ (2S,3S,5R)-2-amino-5-ethyl-1--cyclohexyl-6-hepten-3-ol in 20 ml of methylene chloride a~e added dropwise at -10 to a solution of 5.7 g (9.5 mmol) of (Fmoc)2His-OH, 2.2 g of EDC and 1.75 g of HOBT in a mixture of 40 ml of dimethylformamide and 80 ml of methylene chloride. ~fter completion of the addition the reaction mixture is stirred at -10 for 2 houcs and at room temperature for 16 hours, ~hereafter poured into 2N
sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extracts are dried over potassium carbonate and evaporated. The residue obtained (7.1 g) is suspended in 100 ml of acetonitrile, treated with 100 ml of diethylamine and stirred at room temperature for 17 hours. Thereafter, the reaction mixture is filtered, the ~iltrate is evaporated and the residue is chromatographe~ on 70 g oi silica gel with methylene chloride and increasing amounts of isopropanol and saturated aqueous ammonia as the eluting agent, whereby there are obtained 1.67 g (48~) of (S)-a-amino-N--[(lS,2S,4R)-l-(cyclohexylmethyl)-4-ethyl-2-hydraxy-5---hexenyl~imidazole-4-propionamide as an oil, MS: Z63 (M- C7H130) .

In an analogous manner to that described above, by reacting ~2S,3S,5S)-2--amino-5-ethyl-1-cyclohexyl-6--hepten-3-ol ~ith (Fmoc)2His-OH and cleaving off the Fmoc protecting groups with diethylamine there was obtained (S)-a-amino-N-[(lS,2S,4S)-l-cyclohexylmethyl)--2-hydroxy-4-Pthyl-5-hexenyl]imidazole-4-propionamide as a yellowish solid, MS: 377 (M~H) .

Example 15 0.30 g (0.48 mmol) of t-butyl r(S)-a-[r(S)-l-[[(lS, 2S,4R)-l-(cyclohexylmethyl)-2-hydroxy-4-ethyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethylcaEbamoyl]phenethyl]-~ Gi -i , ~, ,, carbamate in 3 ml o methanol is hydrogenated at room temperature and atmospheric pressure for 7.5 hours in the presence of 60 mg of palladium on charcoal (5%). After completion of the hydrogen uptake the catalyst is filtered off and the ~iltrate is evaporated, whereby there is obtained 0.20 g (66.5%) of t-butyl [(S)-a-[[(S)-l--[[(lS,2S)-l-(cyclohexylmethyl)-2-hydroxy-4-ethylhexyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]-carbamate as a white amorphous solid, MS: 626 (M+H) .

Example 16 0.55 g (1.05 mmol) of (S)-N-[(lS,2S,4R)-l-(cyclohexyl-methyl)-2-hydroxy-4-ethyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide in 5 ml of methylene chloride is added dropwise at -10 to a solution of 0.23 g (1.05 mmol) of Boc-D-Pro-OH, 0.22 g of EDC and 0.17 g of HOBT in 5 ml of methylene chloride. After completion of the addition the reaction mixtuLe is stirred a~ -10 ~or 2 hours and at room temperature for 18 hours, thereafter poured into 2N sodium bicarbonate solution and extracted with msthylene chloride. The methylene chloride ex~racts are dried over potassium carbonate and evaporated, and the residue is chromatographed on 10 g of silica gel with methylene chloride and increasing amounts o isopropanol as the eluting agent, whereby thers is obtained 0.59 g (78%) of t-butyl (R)-2-~r(S)-a-[t(S)-l-[r(lS,2S,4R)-l--(cyclohexylmethyl)-2-hydroxy-4-ethyl-5-hexenyl]carbamoyl]--2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1--pyrrolidinecarboxylate as an amorphous solid, MS: 721 (M+H) .

The (S)-N- r ( lS,2S,4R)-l-(cyclohexylmethyl)-2-hydroxy--4-ethyl-5-hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide used as the starting material was prepared as follows:

2~ 7~

0.60 g (1.5~ mmol) of (S)-a-amino-N-r(lS,2S,4R)-l--(cyclohexylmethyl)-4-ethyl-Z-hydroxy-5-hexenyl~imidazole--4-propionamide in 7.5 ml of methylene chloride i~ added dropwise at -10 to a solution of 0.62 g (1.59 mmol) of Fmoc-Phe-OH, 0.33 g o~ EDC and 0.24 g of HOBT in 7.5 ml of methylene chloride. A~ter completion of the addition the reaction mixture is stirred at -10 for 2 hours and subsequently at room temperature for 17 hours, therea~ter poured into 2N sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride extrac~s are dried over potassium carbonate and eva~orated, and the residue is chromatographed on 15 g of silica gel with methylene chloride and increasing amounts o~ isopropanol as the eluting agent. The thus-obtained crystalline product (0.90 g) is suspended in 12.5 ml of acetonitrile and subsequently treated with 12.5 ml o~ diethylamine.
Thereafter, the reaction mixture is stirred at room temperature for 75 minutes and then evaporated, a~d the residue is chromatographed on 10 g of silica gel with methylene chloride and increasing amounts of isopropanol and saturated ammonia solution as the eluting agent, whereby there is obtained 0.62 g (74.5%) of (S)-N- r (lS, 2S,4R)-l-(cyclohexylmethyl~~2-hydroxy-4-ethyl-5-hexenyl]--a-(3-phenyl--L-alanyl)imidazole-4-propionamide as an amorphous, white solid, MS: 524 (M+H) .

ExamPle 17 ln an analogous manner to that described in Example 15, by catalytically hydrogenating t-butyl (R)-2--[[(S)-a-[[(S)-l-[[(lS,2S,4R)-l-(cyclohexylmethyl)-2--hydroxy-4-ethyl-5-hexenyl]carbamoyl]-2-imidazol-~-yl-ethyl]carbamoyl]phenethyl]carbamoyl]-l-pyrrolidine--carboxylate there wa obtained t-butyl (R)-2-[r(S)-a--r[(s)-l-[r(ls~2s)-l-(cyclohexylmethyl)-2-hydroxy-4-ethyl-hexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]-2 ~

carbamoyl]-l-pyrrolidinecarboxylate as an amorphous, white solid, MS: 723 (M~H) .

Example 18 The following compounds were manufactured in an analogous manner to that described in Example 14:

- From (S)-a-amino-N-[(lS,2S,4R)-l-(cyclohexyl-methyl)-4-ethyl-~-hydroxy-5-hexenyl]imidazole-4-prcpion-amide and (R)-a- (pivaloylmethyl)hydrocinnamic acid the (S)-N-[~lS,2S,4R)-l-(cyclohexylmethyl)-4-ethyl-2-hydroxy--5-hexenyl]-a-r(R)---(3,3-dimethyl-2-oxobutyl)hyd~o-cinnamamido]imidazole-4-propionamide as a white foam, MS:
607 (M~H) , and - from (S)-a-amino-N-r(lS,2S,4R)-l-(cyclohexyl-methyl)-4-ethyl-2--hydroxy-5-hexenylJimidazole-4-propion-amide and a-[(t-butylsulphonyl)methyl]hydrocinnamic acid the (S) -a- r (S)-a- r ( ~-butylsulphonyl)methyl]hydro-cinnamamido]-N-r(lS,2S,4R)-l-(cyclohexylmethyl)-4-ethyl-2--hydroxy-5-hexanyl]imidazole-5-propionamide as a solid, MS: 657 (M~H) .
Example 19 In an analogous manner to that described in Example 15, by catalytically hydrogenating (S)-a-r(S)--a-r(t-butylsulphonyl~methyl]hydrocinnamamido]-N-r(lS, 2S,4R)-1 (cyclohexylmethyl)-4-ethyl-2-hydroxy-5-hexenyl]-imidazole-5-propionamide there was obtained (S)-a-~(S)--a-r(t-butylsulphonyl)methyl]hydrocinnamamido]-N-r(lS,2S, 4R)-l-(cyclohexylmethyl)-4-ethyl-2-hydroxyhexyl]imidazole--5-propionamide as an amorphous, white solid, MS: 645 ~M~H) -Example ~

A sterile-filtered aqueous solution of t-butyl (R)-2--~[tS)-a-~r(S)-l-[[(lS,2S,4~)-1-(cyclohexylmethyl)-2--hydroxy-4-ethyl-5-hexenyl]carbamoyl]-2-imidazol-4-yl-ethyl]carbamoyl]phenethyl]carbamoyl]-l-py~rolidine-carboxylate is mixed while warming with a sterile gelatine solution, which contains phenol as a preserving agent, under aseptic conditions so tha~ 1.0 ml of solution has the following composition:

t-Butyl (R)-2-r[(S)-a[[(s)-l-15 -[[(lS,2S,4R)-l-(cyclohexylmethyl)--2-hydroxy-4-ethyl-5-hexenyl]carbamoyl]--2-imidazol-4-ylethyl]carbamoyl]-phenethyl]carbamoyl]-l-pyrrolidine-carboxylate 3.0 mg 20 Gelatine 150.0 mg Phenol ~.7 mg Dist. water ad 1.0 ml The mixture is filled into 1.0 ml vials under aseptic conditions.
ExamPle B

5 mg of t-butyl (R)-2-[[(S)-a[[(S)-l-[~(lS,2S,~R)-l--(cyclohexylmethyl)~l-hydroxy-4-sthyl-5-hexenyl]carbamoyl]--2-imidazol-4-ylethyl3carbamoyl]phenethyl]carbamoyl3-1--pyrrolidinecarboxylate are dissolved in 1 ml of an aqueous solu~ion with 20 mg of mannitol. The solution is filtered sterile and filled under aseptic conditions into a 2 ml ampoule, cooled to a low temperature and lyophilized. Prior to administration the lyophilizate is dissolved in 1 ml of distilled water or 1 ml of physio-logical saline. The solution is used intramuscularly or 2~13~7~

int~avenously. This formulation can also be fiiled into double chamber injection ampoules.

Example C

50~ mg of finely milled (5.0 ~m) t-butyl (R)-2--~(S)-a-~t(S)-l-~(lS,2S,4R)-l-(cyclohexylmethyl)-Z--hyd~oxy-4-ethyl-5-hexenyl]carbamoyl~-2-imidazol-4-yl-ethyl]carbamoyl]phenethyl]carbamoyl~-l-pyrrolidine-carboxylate are suspended in a mixture of 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. This suspension is filled into a container having a dosage valve. 5.0 g o Freon 12 are filled into the container through the ~alve under pressure. ~he Freon is dissolved in the Myglyol--benzyl alcohol mixture by shaking. This spray container contains about 100 individual dosages which can be applied individually.

ExamPle D

When the pro~edures described in Examples A-C are followed, cor~esponding galenical preparations can be manufactured from the following, likewise preferred, compound~:

t-Butyl (R)-2-[~(S)-a-[[(S)-l-[[(lS,2S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-ethylhexyl]carbamoyl]-Z-imidazol--4-ylethyl]carbamoyl]phene~hyl]Jcarbamoyl]-l-pyrrolidine-carboxylate (S)-N-[(lS,2S,4R)-l-(cyclohexylmethyl)-4-ethyl-2--hydroxy-5-hexenyl]-a-[(R)-a-(3,3-dimethyl-2-oxo-butyl)-hydrocinnamamido~imidazole-4-propionamide, (S)-a-[(S)-a-[(t-butylsulphonyl)methyl]hydrocinnam-amido]-N-[(lS,2S,4R)-l-(cyclohexylmethyl)-4-ethyl-2--hydroxy-5-hexenyl]imidazole-5-pLopionamide;

7~

t-butyl t(S)-a-[[(s)-l- r [ (lS, 2R or 2S)-3-cyclohexyl--l-(cyclohexylmethyl)-2-hydroxypropyl]carbamoyl]-2--imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate;

(2R or S,3S)-3-(Boc-D-Pro-Phe-His-NH)-1,4-dicyclo-hexyl-2-butanol and (S)-N-[(lS,2S)-l-(cyclohexylmethyl)-4-ethyl-4-fluoro--2-hydroxyhexyl]-a-r(R)-a-(3,3-dimethyl)-2-oxobutyl)-hydrocinnamamido]imidazole-4-propionamide.

Claims (26)

1. Amino acid derivatives of the general formula I

wherein R1 signifies hydrogen or methyl, R2 signifies ethyl, propyl, isopropyl, imidazol-2-yl, imidazol-4-yl, pyrazol-3-yl, thiazol-4-yl, thien-2-yl, ethoxycarbonyl, t-butylcarbonylmethyl, benzyloxy-carbonylmethyl or t-butoxy, R3 signifies isobutyl, cyclohexylmethyl or benzyl, R4 signifies hydroxy or amino, R5 signifies alkyl, haloalkyl, cycloalkyl, alkenyl, aryl or heteroaryl, n signifies 0, 1, 2, 3, 4, 5 or 6 and A signifies one of the groups (a) and -Y-Z (b) in which the dotted line can signify an additional bond, R6 signifies phenyl, substituted phenyl, benzyl or naphthyl and R7 signifies hydrogen, alkoxycarbonylalkyl, alkylcarbonylalkyl, cycloalkyl-carbonylalkyl, heterocycloalkylcarbonylalkyl, aryl-carbonylalkyl, aminocarbonylalkyl, substituted amino-carbonylalkyl, aminoalkylcarbonylalkyl, substituted aminoalkylcarbonylalkyl, aminoalkylsulphonylalkyl, substituted aminoalkylsulphonylalkyl, alkoxycarbonyl-hydroxyalkyl, alkylcarbonylhydroxyalkyl, cycloalkyl-carbonylhydroxyalkyl, hetecocycloalkylcarbonylhydroxy-alkyl, arylcarbonylhydroxyalkyl, aminocarbonylhydroxy-alkyl, substituted aminocarbonylhydroxyalkyl, dialkoxyphosphoroxyalkyl, diphenyloxyphosphoroxyalkyl, arylalkyl, alkoxycarbonylamino, arylalkoxycarbonyl-amino, alkylthioalkyl, alkylsulphinylalkyl, alkyl-sulphonylalkyl, arylthioalkyl, arylsulphinylalkyl, arylsulphonylalkyl, arylalkylthioalkyl, arylalkyl-sulphinylalkyl or arylalkylsulphonylalkyl, Y signifies the bivalent residue of optionally N- and/or .alpha.-methylated phenylglycine, cyclohexylglycine, phenylalanine, cyclohexylalanine, 4-fluorophenyl-alanine, 4-chlorophenylalanine, tyrosine, O-methyl-tyrosine, .alpha.-naphthylalanine or homophenylalanine linked with Z at the N terminal and Z signifies hydrogen or acyl, with the provisos that (i) R5 does not signify alkyl, cycloalkyl or aryl where n signifies 2, 3, 4, 5 or 6, (ii) the carbon atom of alkyl which is attached to the CH2 group is branched where n signifies 1 and R5 signifies alkyl, (iii) the carbon atom of R5 attached to the carbon atom carrying the substituent R4 has no methylene group in the .alpha.-position where n signifies O and R5 signifies alkyl.
(iv) R5 does not signify alkyl where R2 signifies imidazol-4-yl, R4 signifies hydroxy and Y signifies phenylalanine and (v) R7 does not signify alkoxycarbonylamino or arylalkoxycarbonylamino where R6 signifies phenyl, benzyl or .alpha.-naphthyl, in the form of optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts of these compounds.

2. Compounds in accordance with claim 1, wherein R1 signifies hydrogen.

3. Compounds in accocdance with claim 1 or 2, wherein R2 signifies imidazol-2-yl, imidazol-4-yl or thiazol 4-yl, especially imidazol-4-yl.

4. Compounds in accordance with any one of claims 1-3, wherein R3 signifies cyclohexylmethyl.

5. Compounds in accordance with any one of claims 1-4, wherein R4 signifies hydroxy.

6. Compounds in accordance with any one of claims 1-5, wherein R5 signifies alkyl, haloalkyl, cycloalkyl or alkenyl, especially 3-pentyl, fluoroalkyl, cyclohexyl or 3-pentenyl.

7. Compounds in accordance with any one of claims 1-6, wherein n is 0 or 1, especially 1.

8. Compounds in accordance with any one of claims 1-7, wherein A signifies group (a).

9. Compounds in accordance with claim 8, wherein R6 signifies phenyl or substituted phenyl, especially phenyl.

10. Compounds in accordance claim 8 or 9, wherein R7 signifies alkylcarbonylalkyl, aminoalkylcarbonyl-alkyl, substituted aminoalkylcarbonylalkyl, aminoalkyl-sulphonylalkyl, substituted aminoalkylsulphonylalkyl or alkylsulphonylalkyl, especially alkylcarbonylalkyl or alkylsulphonylalkyl, particularly C1-C4-alkylcarbonyl-methyl or C1-C4-alkylsulphonylmethyl.

11. Compounds in accordance with any one of claims 1-7, wherein A signifies group (b) and Y signifies the bivalent residue of phenylalanine linked with Z at the N-terminal.

12. Compounds in accordance with claim 11, wherein Z
signifies the group Ra-O-CO- or the residue of an .alpha.-amino acid, especially proline, which is acylated by this group, in which Ra signifies an optionally substituted, saturated aliphatic hydrocarbon residue with up to 10 cacbon atoms or an optionally substituted heteroaromatic hydrocarbon residue with up to 18 carbon atoms, especially a saturated aliphatic hydrocarbon residue with up to 6 carbon atoms.

13. Compounds in accordance with claim 1, wherein R1 signifies hydrogen, R2 signifies imidazol-4-yl, R3 signifies cyclohexylmethyl, R4 signifies hydroxy, R5 signifies 3-pentyl, fluoroalkyl, cyclohexyl or 3-pentenyl, n signifies 1, R6 signifies phenyl, R7 signifies C1-C4-alkylcarbonylmethyl or C1-C4--alkylsulphonylmethyl, Y signifies the bivalent residue of phenylalanine linked with Z at the N-terminal and Z
signifies the group RA-O-CO- or the residue of proline which is acylated by this group, wherein Ra signifies a saturated, aliphatic hydrocarbon residue with up to 6 carbon atoms.

14. t-Butyl (R)-2-[[(s)-.alpha.-[[(S)-l-[[(lS.2S.4R)-l--(cyclohexylmethyl)-2-hydroxy-4-ethyl-5-hexenyl]carbamoyl]--2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-l--pyrrolidinecarboxylate, t-hutyl (R)-2-[[(S)-.alpha.-[[(S)-l--[[(lS,2S)-l-(cyclohexylmethyl)-2-hydroxy-4-ethylhexyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]-carbamoyl]-l-pyrrolidinecarboxylate, (S)-N-[(lS,2S,4R)-l--(cyclohexylmethyl)-4-ethyl-2-hydroxy-5-hexenyl]-.alpha.-[(R)--.alpha.-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole--4-propionamide, (S)-.alpha.-[(S)-.alpha.[(t-butylsulphonyl)-methyl]hydrocinnamamido]-N-[(1S,2S,4R)-l-(cyclohexyl-methyl)-4-ethyl-2-hydroxy-5-hexenyl]imidazole-5-propion-amide, t-butyl [(S)-.alpha.-[[(S)-l-[[(1S,2R or 2S)-3-cyclo-hexyl-l-(cyclohexylmethyl)-2-hydroxypropyl]carbamoyl]-2--imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate, (2R or S,3S)-3-(Boc-D-Pro-Phe-His-NH)-1,4-dicyclohexyl-2-butanol or (S)-N-[(lS,2S)-l-(cyclohexylmethyl)-4-ethyl-4-fluoro-2 -hydroxyhexyl]-.alpha.-[(R)-.alpha.-(3,3-dimethyl-2-oxobutyl)hydro-cinnamamido]imidazole-4-propionamide.

15. Compounds of the formulae II III

V VI

and VII XIV

wherein R1 signifies hydrogen or methyl, R2 signifies ethyl, propyl, isopropyl, imidazol-2- yl, imidazol-4-yl, pyrazol-3-yl, thiazol-4-yl, thien-2-yl, ethoxycarbonyl, t-butylcarbonylmethyl, benzyloxy-carbonylmethyl or t- butoxy, R3 signifies isobutyl, cyclohexylmethyl or benzyl, R5 signifies alkyl, haloalkyl, cycloalkyl, alkenyl, aryl or heteroaryl, n signifies 0, 1, 2, 3, 4, 5 or 6 and A signifies one of the groups (a) and -Y-Z (b) in which the dotted line can signify an additional bond, R6 signifies phenyl, substituted phenyl, benzyl or naphthyl and R7 signifies hydrogen, alkoxycarbonylalkyl, alkylcarbonylalkyl, cycloalkyl-carbonylalkyl, heterocycloalkylcarbonylalkyl, aryl-carbonylalkyl, aminocarbonylalkyl, substituted amino-carbonylalkyl, aminoalkylcarbonylalkyl, substituted aminoalkylcarbonylalkyl, aminoalkylsulphonylalkyl, substituted aminoalkylsulphonylalkyl. alkoxycarbonyl-hydroxyalkyl, alkylcarbonylhydroxyalkyl, cycloalkyl-carbonylhydroxyalkyl, heterocycloalkylcarbonylhydroxy-alkyl, arylcarbonylhydroxyalkyl, aminocarbonylhydroxy-alkyl, substituted aminocarbonylhydroxyalkyl, dialkoxyphosphoroxyalkyl, diphenyloxyphosphoroxyalkyl, arylalkyl, alkoxycarbonylamino, arylalkoxycarbonyl-amino, alkylthioalkyl, alkylsulphinylalkyl, alkyl-sulphonylalkyl, arylthioalkyl, arylsulphinylalkyl, arylsulphonylalkyl, arylalkylthioalkyl, arylalkyl-sulphinylalkyl or arylalkylsulphonylalkyl, Y signifies the bivalent residue of optionally N- and/or .alpha.-methylated phenylglycine, cyclohexylglycine.

phenylalanine, cyclohexylalanine, 4-fluorophenyl-alanine, 4-chlorophenylalanine, tyrosine, O-methyl-tyrosine, .alpha.-naphthylalanine or homophenylalanine linked with Z at the N-terminal and Z signifies hydrogen or acyl, with the provisos that (i) R5 does not signify alkyl, cycloalkyl or aryl where n signifies 2, 3, 4, 5 or 6, (ii) the carbon atom of alkyl which is attached to the CH2 group is branched where n signifies 1 and R5 signifies alkyl, (iii) the carbon atom of R5 attached to the carbon atom carrying the substituent R4 has no methylene group in the .alpha.-position where n signifies O and R5 signifies alkyl, (iv) R5 does not signify alkyl where R2 signifies imidazol-4-yl, R4 signifies hydroxy and Y signifies phenylalanine and (v) R7 does not signify alkoxycarbonylamino or arylalkoxycarbonylamino where R6 signifies phenyl, benzyl or .alpha.-naphthyl, R41 signifies hydroxy or N-protected amino and R21 signifies ethyl, propyl, isopropyl, thiazol-4-yl, thien-2--yl, ethoxycarbonyl, t-butylcarbonylmethyl, benzyloxy-carbonylmethyl, t-butoxy or optionally N-protected imidazol-2-yl, imidazol-4-yl or pyrazol-3-yl, with the proviso that at least one of R41 and R21 contains a N-protecting group, R42 signifies N-protected amino, R51 signifies alkyl, cycloalkyl, alkenyl, aryl or heteroaryl and B signifies an amino protecting group.

16. Amino acid derivatives in accordance with any one of claims 1-14 for use as therapeutically active substances.

17. Amino acid derivatives in accordance with any one of claims 1-14 for use in the control or prevention of high blood pressure and cardiac insufficiency.

18. A process for the manufacture of a compound in accordance with any one of claims 1-14, which process comprises a) for the manufacture of a compound of formula I in which R4 signifies hydroxy and the remaining symbols have the significance given in claim 1, reacting a compound of the general formula II

wherein R1, R2, R3, R5 and n have the significance given in claim 1, with an acylating agent yielding the group (a) or -Y-Z (b) wherein R6, R7, Y, Z and the dotted line have the significance given in claim 1, or b) for the manufacture of a compound of formula I in which R4 signifies hydroxy and the remaining symbols have the significance given in claim 1, reacting a compound of the general formula III

wherein R3, R5 and n have the significance given in claim 1, with a compound of the general formula IV

wherein R1, R2 and A have the significance given in claim 1, or an activated derivative thereof, or c) for the manufacture of a compound of formula I in which A signifies group (b), Z signifies the monovalent residue of an optionally acylated amino acid or of an optionally acylated dipeptide attached via the carboxyl group and R signifies hydroxy and the remaining symbols have the significance given in claim 1, reacting a compound of formula I in which Z signifies hydrogen and the remaining symbols have the significance given in claim 1 with an optionally acylated amino acid or an optionally acylated dipeptide, or d) for the manufacture of a compound of formula I in which A contains a free amino group and/or R4 signifies amino and/or R2 signifies imidazol-2-yl, imidazol-4-yl or pyrazol-3-yl, cleaving off the N-protecting group(s) from a corresponding compound of formula I in which A
contains a N-protected amino group and/or from a compound of the general formula V

wherein R41 signifies hydroxy or N-protected amino and R21 signifies ethyl, propyl, isopropyl, thiazol--4-yl, thien-2-yl, ethoxycarbonyl, t-butylcarbonyl-methyl, benzyloxycarbonylmethyl, t-butoxy or optionally N-protected imidazol-2-yl, imidazol-4-yl or pyrazol-3-yl and the remaining symbols have the significance given in claim 1, with the proviso that at least one of R41 and R21 contains a N-protecting group, and e) if desired, separating a mixture of diastereomers racemates into the diastereomeric racemates or optically pure diastereomers, and/or f) if desired, separating a mixture of diastereomers into the optically pure diastereomers, and/or g) if desired, converting a compound obtained into a pharmaceutically usable salt.

19. A medicament containing an amino acid derivative in accordance with any one of claims 1-14 and a therapeu-tically inert excipient.

20. A medicament for the control or prevention of high blood pressure and cardiac insufficiency, containing an amino acid derivative in accordance with any one of claims 1-14 and a therapeutically inert excipient.

21. The use of an amino acid derivative in accordance with any one of claims 1-14 in the control or prevention of illnesses.

22. The use of an amino acid derivative in accordance with any one of claims 1-14 in the control or prevention of high blood pressure and cardiac insufficiency.

23. The use of an amino acid derivative in accordance with any one of claims 1-14 for the manufacture of medicaments against high blood pressure and/or cardiac insufficiency.

24. Amino acid derivatives in accordance with any one of claims 1-14, whenever prepared according to the process as claimed in claim 18 or by an obvious chemical equi-valent thereof.

25. The invention as hereinbefore described.

26. A method of treating or preventing high blood pressure and/or cardiac insufficiency which comprises administering to a patient requiring such treatment an effective amount of an amino acid derivative in accordance with any one of claims 1-14.

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