NZ226395A - Renin-inhibiting amino acid derivatives and pharmaceutical compositions - Google Patents

Renin-inhibiting amino acid derivatives and pharmaceutical compositions

Info

Publication number: NZ226395A
Authority: NZ; New Zealand
Prior art keywords: hydroxy; acid; hexenyl; carbamoyl; imidazole
Prior art date: 1987-10-06

Application number

NZ226395A

Inventor

Quirico Branca

Albrecht Edenhofer

Eva-Maria Gutknecht

Werner Neidhart

Henri Ramuz

Wolfgang Wostl

Original Assignee

Hoffmann La Roche

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1987-10-06

Filing date

1988-09-29

Publication date

1991-12-23

1988-09-29 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

1991-12-23 Publication of NZ226395A publication Critical patent/NZ226395A/en

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
General Chemical & Material Sciences (AREA)
Public Health (AREA)
Molecular Biology (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Veterinary Medicine (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Engineering & Computer Science (AREA)
Biochemistry (AREA)
Biophysics (AREA)
Genetics & Genomics (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Peptides Or Proteins (AREA)
Plural Heterocyclic Compounds (AREA)
Furan Compounds (AREA)
Pyridine Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Indole Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £26395 22 6 39 5 Priority Compete Speciftemkm Filed: (5). <142^1^-5 {C2Ca{.Q.%.t.l£i.r . <cCiTlCXX./o>fj..c^orT.C.X 20. ./.O &..f CO.T10. Xw>^ [Co 4+- f - • ^ jjg. l|D I ■/•(•>• f Publication fete: Buma!, - Mo: •> 15.5.1 P.O. JtU-'iTri I Glass Cont: <T.©"TlC>t4-Qt2l/./.^.y 13 [(JUf. AGs (*C3> I /i^ .MS ^sa, £:?/&(*,. con fb co'lDiir^ ^r— —-—NfiWZEALAND patents act, 1953 Complete specification AMINO ACID DERIVATIVES -1/We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss Company hereby declare the invention for which-I-/ we pray that a patent may be granted to pfte-/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) 226395 - la - The present invention is concerned with amino acid derivatives. In particular, it is concerned with amino acid derivatives of the general formula £ 9 f .« »VyYY V r ch3 ch3 1 2 wherein R signifies hydrogen or methyl. R signifies ethyl, propyl or imidazol-4-yl. R3 signifies 4 isobutyl. cyclohexylmethyl or benzyl. R signifies phenyl, furyl. vinyl, ethyl or 1.2-dihydroxyethyl and A signifies dibenzsuberaneacetic acid. 2-(2-pyridyl)-benzoic acid, fi-naphthylsuccinic acid monoethyl ester. 2-indolylacetic acid or dihydrocinnamic acid attached via the carboxyl group or one of the groups R6 R5 f R \ W -Y-Z • i (a) and (b) in which the dotted line can signify an additional 5 bond, R signifies phenyl, naphthyl. indolyl. pyrazolyl. imidazolyl or pyridylmethyl and R6 22 6 3 9 5 - 2 - signifies hydrogen, alkyl. arylalkyl. alkoxycarbonyl-alkyl. alkylcarbonylalkyl. cycloalkylcarbonylalkyl, heterocycloalkylcarbonylalkyl. arylcarbonylalkyl. aminocarbonylalkyl, substituted aminocarbonylalkyl, aminocarbonyl. substituted aminocarbonyl, alkoxy-carbonyl. alkylcarbonyloxy. arylalkylcarbonyloxy. alkylaminocarbonyloxy. alkoxycarbonylamino, cyano or 4 2,5-dimethylpyrrol-l-yl, with the proviso that R 3 can not signify alkoxycarbonylamino when R signifies phenyl or a-naphthyl, and Y signifies a bivalent residue of optionally N- and/or a-methylated phenylglycine. cyclohexylglycine. phenylalanine, cyclohexylalanine, 4-fluorophenyl-alanine. 4-chlorophenylalanine. tyrosine, a-naphthylalanine. homophenylalanine. aspartic acid ethyl ester, glutamic acid t-butyl ester or glutamic acid benzyl ester linked with Z at the N-terminal and Z signifies hydrogen, acyl or one of the groups (. >"ch2— <rH-CH2- ,NH ft — • SS /•-CH--OC-N-C- CH3"SVU 2 • — < (c) (d) and (e) , 30 in the form of optically pure diastereomers, diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts of these compounds. 35 These compounds are novel and are distinguished by valuable pharmacodynamic properties. 226395 10 - 3 - Objects of the present invention are the compounds of formula I and their pharmaceutically usable salts per se and for use as therapeutically active substances, the manufacture of these compounds, medicaments containing these and the manufacture of such medicaments. Also disclosed is the use of compounds of formula I and their pharmaceutically 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 term "alkyl" used in the present description -alone or in combination - signifies straight-chain and branched, saturated hydrocarbon 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" 2° signifies alkyl ether 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 term "cycloalkyl" signifies saturated, cyclic hydrocarbon residues with 3-8, preferably 3-6, 25 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "heterocycloalkyl" relates in the same manner to saturated. 3-8-membered. preferably 5- or 6-membered. cyclic hydrocarbon residues in which one or two methylene groups is/are replaced by 30 one or two oxygen, sulphur or optionally alkyl-. phenylalkyl-, alkanoyl- or alkanoyloxy-substituted nitrogen atoms, such as piperidinyl, pyrazinyl. N-benzyl-pyrazinyl, morpholinyl. N-methylpiperidinyl. N-benzyl-morpholinyl and the like. The term "aryl" denotes a 35 mono- or bicyclic aromatic hydrocarbon residue with 6-14 carbon atoms which is optionally mono- or multiply--substituted by alkyl, alkoxy, alkanoyloxy. amino, alkylamino. dialkylamino. alkanoylamino. hydroxyrha^fcegen, •iff! ' I? 22 6 3 9 5 10 _ 4 - trifluoromethyl or nitro. such as phenyl, a- or fl-naphthyl. indenyl. anthryl or phenanthryl and the like. The term "arylalkyl" denotes straight-chain or branched alkyl groups in which one or more hydrogen atoms is/are replaced by aryl groups, such as benzyl, diphenylmethyl. trityl. a- or fl-naphthylmethyl. 2-phenylethyl. 3-phenyl- -2-propyl. 4-phenyl-3-butyl. 2-(a- or fl-naphthyl)ethyl. 3-a-naphthyl-2-propyl, 4-a-naphthyl-3-butyl and the like, whereby the aromatic residue can in each case be mono- or multiply-substituted as indicated above. The term "substituted amino" signifies an amino group which is mono- or di-substituted by alkyl. arylalkyl, alkanoyl. 15 alkoxycarbonyl or arylalkoxycarbonyl or disubstituted by C3-C6-alkylene which is optionally interrupted by an oxygen, sulphur or alkyl-, phenylalkyl-. alkanoyl- or alkanoyloxy-substituted nitrogen atom. The term "acyl" relates to the acyl group of a carboxylic acid, of a half 20 ester of carbonic acid, of an optionally N-substituted carbamic or thiocacbamic acid, of an optionally N-substituted oxalamide, of a sulphonic acid or of an optionally N-substituted amidosulphonic acid, especially b a those with the partial formulae R -CO-, R -O-CO-, 25 (Rb)(Rb)N-CO-. (Rb)(Rb)N-CS-. (Rb)(Rb)N-CO-CO-, Rb-S02-. or (Rb)(Rb)N-S02- in which Ra signifies an unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic hydro-30 carbon residue with up to 18, preferably 10. carbon atoms, 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 35 heterocycle and Rb signifies hydrogen or has the significance of Ra. The term "acyl" also relates to the monovalent residue of an amino acid, of a dipeptide or of a tripeptide attached via the carboxyl group. ^^6 3 - 5 - An unsubstituted or substituted, saturated or unsaturated, aliphatic, cycloaliphatic or cycloaliphatic- a b -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 atoms can be substituted by hydroxy, alkoxy. aryloxy. alkanoyloxy. halogen, hydroxysulphonyloxy, carboxy, alkoxycarbonyl. carbamoyl, alkylcarbaraoyl, dialkylcarbamoyl. cyano, phosphono. esterified phosphono. amino or oxo. whereby the substituents are present in the 1-position of the alkyl residue only when this is attached to the carbonyl group b in the partial formula R -CO-. Examples of substituted alkyl are 2-hydroxyethyl. methoxymethyl. 2-methoxyethyl. phenoxymethyl. a- or B-naphthoxymethyl, acetoxymethyl. 2-acetoxyethyl, chloro-methyl. bromomethyl. 2-chloro- or 2-bromoethyl. hydroxy-sulphonyloxymethyl, 2-hydroxysulphonyloxyethyl. carboxy-methyl. 2-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. hydroxymethoxycarbonylethyl. acetoxymethoxycarbonylmethyl. 1.2-dihydroxy-2-carboxyethyl. 1.2-dihydroxy-2-ethoxy-carbonylethyl, 1.2-dihydroxy-2-methoxycarbonylethyl. 1.2--diacetoxy-2-ethoxycarbonylethyl. 1.2-diacetoxy-2-methoxy-carbonylethyl. l-a-naphthoxy-3-carboxypropyl. 1-a--naphthoxy-2-ethoxycarbonylethyl. l-a-naphthoxy-3-t--butoxycarbonylpropyl. l-a-naphthoxy-2-benzyloxy-carbonylethyl, l-a-naphthoxy-3-carbamoylpropyl. 22 6 3 9 5 - 6 - a-naphthoxycyanomethyl. l-a-naphthoxy-3-cyanopropyl. l-a-naphthoxy-4-dimethylaminobutyl or l-a-naphthoxy-3-5 -oxobutyl. The term "alkenyl" relates to straight-chain or branched, unsaturated hydrocarbon residues with 2-8. preferably 2-4. carbon atoms, whereby the double bond is 10 present in the 1-position of the alkenyl residue only when this is attached to the carbonyl group in the partial formula R -CO-. Examples of such alkenyl residues are vinyl, allyl. 2-butenyl or 3-butenyl. The alkenyl residues can be substituted by the same substituents as the alkyl 15 residues. The term "alkynyl" relates to hydrocarbon residues with 2-8, preferably 2-4, carbon atoms which contain a triple bond, such as ethynyl. 1-propynyl or 2-propynyl. 20 The term "bicycloalkyl" relates to bicyclic saturated hydrocarbon residues with 5-10. preferably 6-9. carbon atoms such as bicyclo[3.1.0]hex-l-yl. bicyclo[3.1.0]hex-2--yl, bicyclo[3.1.0]hex-3-yl, bicyclo[4.1.0]hept-l-yl, bicyclo[4.1.0]hept-4-yl, bicyclo[2.2.l]hept-2-yl, 25 bicyclo[3.2.lJoct-2-yl. bicyclo[3.3.0]oct-3-yl. bicyclo[3.3.lJnon-9-yl. a- or fl-decahydronaphthyl and the like. The term "tricycloalkyl" relates to a tricyclic 30 saturated hydrocarbon residue with 8-10 carbon atoms such as 1-adamantyl. The term "cycloalkenyl" relates to an unsaturated cyclic hydrocarbon residue with 3-8, preferably 3-6, 35 carbon atoms such as 1-cyclohexenyl. 1.4-cyclohexadienyl and the like. 22 6 3 9 5 - 7 - 10 15 20 The term "bicycloalkenyl" relates to a bicyclic unsaturated hydrocarbon residue with 5-10, preferably 7-10. carbon atoms such as 5-norbornen-2-yl, bicyclo-[2.2.2]octen-2-yl, hexahydro-4.7-methanoind-l-en-6-yl and the like. Examples of cycloalkylalkyl are cyclopropylmethyl. cyclobutylmethyl. cyclopentylmethyl. cyclohexylmethyl and the like. Cyclohexylvinyl and cyclohexylallyl and the like can be named as examples of cycloalkylalkenyl. Examples of cycloalkenylalkyl are 1-cyclohexenylmethyl. 1,4-cyclohexa-dienylmethyl and the like. The mentioned cycloaliphatic and cycloaliphatic--aliphatic residues can be substituted by the same substituents as alkyl. An optionally substituted 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-(fl-naphthyl)vinyl and the like are examples of aryl-25 alkenyl. In a heteroaromatic or heteroaromatic-aliphatic hydrocarbon residue the heterocycle is mono-, bi- or tricyclic and contains one to two nitrogen atoms and/or one oxygen 30 or sulphur atom and is linked with the group -CO-. -0-C0-, >N-CO-, >N-CS-, >N—CO-CO-. -S02 or >N-SOz- with one of its ring carbon atoms. Examples of such heteroaromatic hydrocarbon residues are pyrrolyl. furyl. thienyl. imidazolyl. pyrazolyl. oxazolyl. thiazolyl. pyridyl. 35 pyrazinyl. pyrimidinyl. indolyl. quinolyl. isoquinolyl. quinoxalinyl. fl-carbolinyl or a benz-fused. cyclopenta-. cyclohexa- or cyclopenta-fused derivative of these 22 6 39 - 8 - residues. The heteroaromatic residue can be substituted on a nitrogen atom by alkyl. phenyl or phenylalkyl, e.g. benzyl, and/or on one or more carbon atoms by alkyl. phenyl, phenylalkyl. halogen, hydroxy, alkoxy. phenyl-g alkoxy or oxo and can be partially saturated. Examples of such heteroaromatic residues are 2- or 3-pyrrolyl. phenyl-pyrrolyl. e.g. 4- or 5-phenyl-2-pyrrolyl. 2-furyl. 2-thienyl. 2-imidazolyl. 2-. 3- or 4-pyridyl. 2-. 3- or 5-indolyl. substituted 2-indolyl. for example 1-methyl-. 1Q 5-methyl-. 5-methoxy-. 5-benzyloxy-. 5-chloro- or 4.5--dimethyl-2-indolyl. l-benzyl-2-indolyl. l-benzyl-3--indolyl. 4.5.6.7-tetrahydro-2-indolyl, cyclohepta[b]-5--pyrrolyl, 2-. 3- or 4-quinolyl. 4-hydroxy-2-quinolyl. 1-. 3- or 4-isoquinolyl. 1-oxo-l.2-dihydro-3-isoquinolyl. 15 2-quinoxalinyl. 2-benzofuranyl. 2-benzoxazolyl. 2-benz- thiazolyl, benz[e] indol-2-yl. fl-carbolin-3-yl and the like Examples of heteroaromatic-aliphatic hydrocarbon residues are 2- or 3-pyrrolylmethyl. 2-. 3- or 4-pyridyl-2q methyl. 2-(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 heterocycle has at least 25 one carbon atom. 1-3 nitrogen atoms and optionally one oxygen or sulphur atom as the ring member(s) and is linked with the group -CO- or -0-C0-. >N-CO-. >N-CS-. >N-CO-CO-. -S02- or >N-S02~ with one of its ring carbon atoms. The heterocycle can be substituted on one of its carbon 30 atoms or on a ring nitrogen atom by alkyl. e.g. methyl 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 heterocycles are pyrrolidin-3-yl. 4-hydroxypyrrolidin-35 -2-yl. 5-oxopyrrolidin-2-yl. piperidin-2-yl, piperidin- 22 6 3 $ - 9 - -3-yl. l-methylpiperidin-2-yl. l-methylpiperidin-3-yl. 1-methylpiperidin-4-yl. morphoIin-2-yl. morpholin-3-yl. 5 thiomorpholin-2-yl, thiomorpholin-3-yl, 1,4-dimethyl- piperazin-2-yl. 2-indolinyl. 3-indolinyl, 1,2.3,4-tetra-hydroquinol-2-, -3- or -4-yl. 1,2,3,4-tetrahydro-isoquinol-1-, -3- or -4-yl. l-oxo-1,2.3.4-tetrahydro-isoquinol-3-yl and the like. 10 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 15 lengthened or shortened by one or two methylene groups and/or a methyl group is replaced by hydrogen, substituted aromatic a-amino acids, e.g. substituted phenylalanine or phenylglycine in which the substituent can be alkyl, e.g. methyl, halogen, e.g. fluorine, chlorine, bromine or 20 iodine, hydroxy, alkoxy, e.g. methoxy, alkanoyloxy, e.g. acetoxy, amino, alkylamino, e.g. methylamino. dialkyl-amino, e.g. dimethylamino, alkanoylamino, e.g. acetylamino or pivaloylamino, alkoxycarbonylamino. e.g. t-butoxy-carbonylamino. arylmethoxycarbonylamino. e.g. benzyloxy-25 carbonylamino. and/or nitro and can be present singly or 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 30 acid. e.g. indoline-2-carboxylic acid or 1,2.3,4-tetra-hydroisoquinoline-3-carboxylic acid, a natural or homologous a-amino acid in which a carboxy group in the side-chain is present in esterified or amidated form. e.g. as an alkyl ester group such as methoxycarbonyl or 35 t-butoxycarbonyl or as a carbamoyl, alkylcarbamoyl such as methylcarbamoyl or as a dialkylcarbamoyl group such as dimethylcarbamoyl. in which an amino group of the side- 22 6 3 9 5 - 10 - -chain is present in acylated form. e.g. as alkanyolamino such as acetylamino or pivaloylamino, as alkoxycarbonyl-5 amino such as t-butoxycarbonylamino or as an arylmethoxy-carbonylamino group such as benzyloxycarbonylamino, or in which a hydroxy group of the side-chain is present in etherified or esterified form, e.g. as an alkoxy group such as methoxy. as an arylalkoxy group such as benzyloxy 10 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, isoleucine, norleucine, serine, homoserine. threonine, methionine, 15 cysteine, proline, trans-3- and trans-4-hydroxyproline, phenylalanine, tyrosine, 4-nitrophenylalanine, 4-amino-phenylalanine, 4-chlorophenylalanine, fl-phenylserine. phenylglycine, a-naphthylalanine. cyclohexylalanine, cyclohexylglycine. tryptophan, indoline-2-carboxylic acid. 20 1.2.3.4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine. aminomalonic acid, aminomalonic acid monoamide. glutamic acid, glutamic acid mono-t-butyl ester, glutamine, N-dimethylglutamine, histidine. arginine. lysine, N-t-butoxycarbonyllysine. 25 6-hydroxylysine, ornithine. N-pivaloylornithine. a.y-diaminobutyric acid or a.fl-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. methyl or ethyl, in order to increase the 30 stability of the compound of formula I against enzymatic degradation. The residue of a di- or tri-peptide attached via the carboxyl group consists of two or three of the above-35 -mentioned amino acids. The term "pharmaceutically usable salts" embraces salts with inorganic or organic acids such as hydrochloric 22 6 3 9 5 - n - acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid. C acetic acid, succinic acid, tartaric acid, methane-sulphonic acid, p-toluenesulphonic 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 10 converted into a salt. The compounds of formula I have at least three asymmetric carbon atoms and are therefore present in the form of optically pure diastereomers. diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates. The present invention embraces all forms. Diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates can be separated according to usual methods, e.g. by column chromatography. 20 thin-layer chromatography, HPLC and the like. Those compounds of formula I in which R1 signifies 2 hydrogen are preferred. R preferably signifies imidazol-4-yl. Further, those compounds of formula I in 3 25 which R signifies cyclohexylmethyl are preferred. Also 4 preferred are those compounds of formula I in which R signifies vinyl or ethyl. Likewise preferred are the compounds of formula 1 in which A signifies the group (a) 5 or (b). R preferably signifies phenyl or naphthyl. 30 particularly phenyl. The preferred significance of R6 is alkylcarbonylalkyl, cycloalkylcarbonylalkyl. heterocyclo- alkylcarbonylalkyl, aminocarbonylalkyl or substituted aminocarbonylalkyl, preferably C^-C^-alkylcarbonyl- methyl. C -C -cycloalkylcarbonylmethyl. N-t-butoxy-5 6 35 carbonylpyrrolidinylcarbonylmethyl or aminocarbonylalkyl. which is disubstituted by C1-C4-alkyl or C4~C5~ zze> 395 - 12 - -alkylene optionally interrupted by an oxygen atom or which is monosubstituted by aminoalkyl mono- or disubstituted by alkoxycarbonylalkyl or alkoxycarbonyl. Furthermore, there are preferred the compounds of formula I in which Y signifies the bivalent residue of phenylalanine, cyclohexylalanine, 4-chlorophenylalanine or a-naphthylalanine, particularly phenylalanine, linked with Z at the N-terminal. Z preferably signifies acyl, particularly the residue, linked with Y at the C-terminal, of a N- and/or a-methylated natural amino acid having the L-configuration which is optionally N-substituted by the group R^-CO- or Ra-0-C0- or of an epimer of such an amino acid having the D-configuration or of a dipeptide from two of the above-described amino acids or the group R^-CO- or Ra-0-C0- in which Ra signifies an optionally substituted, saturated or unsaturated aliphatic, cyclo- aliphatic. cycloaliphatic-aliphatic hydrocarbon residue with up to 18 carbon atoms, an optionally substituted aromatic, heteraromatic, aromatic-aliphatic or heteroaromatic-aliphatic hydrocarbon residue with up to 18 carbon atoms or an optionally substituted, saturated 5- or 6-membered heterocycle and Rb signifies hydrogen or has the significance of Ra, particularly a residue, linked with Y at the C-terminal. of proline, prolylproline or histidinylproline, whereby the amino group in each case is substituted by t-butoxycarbonyl, benzoxycarbonyl, b . . b . . . isovaleryl or the group R -CO- in which R signifies a heteroaromatic-aliphatic hydrocarbon residue with up to 10 carbon atoms or a saturated 5- or 6-membered heterocycle. From the above it follows that there are particularly preferred those compounds in which R signifies 2 3 hydrogen. R signifies imidazol-4-yl, R signifies 4 5 cyclohexylmethyl. R signifies vinyl or ethyl and R signifies phenyl and R6 signifies C^-^-alkyl- car bony lme thy 1, C -C -eye loa Iky lea r bony line t 5 6 22 6 3 9 5 - 13 - N-t-butoxycarbonylpyrrolidinylcarbonylmethyl or aminocarbonylalkyl. which is disubstituted by C^C^-alkyl or C-C -alkylene optionally interrupted by an oxygen 4 5 atom or which is mono-substituted by aminoalkyl mono- or di-substituted by alkoxycarbonylalkyl or alkoxycarbonyl. or Y signifies the bivalent residue of phenylalanine linked with Z at the N-terminal and Z signifies the residue of proline, prolylproline or histidinylproline linked with Y at the C-terminal. whereby the amino group in each case is substituted by t-butoxycarbonyl, benzoxycarbonyl, isovaleryl or the group Rb-CO- in which Rb signifies a heteroaromatic-aliphatic hydrocarbon residue with up to 10 carbon atoms or a saturated 5- or 6-membered heterocycle. Quite especially preferred compounds of formula I are: t-Butyl (R)—2—[[(S)-a-[[(S)-1-[(1S.2S.4S)-1-(cyclohexylmethyl ) -2 -hydroxy- 4- isopropylhexyl ] -2- imidazo 1-4--ylethyl]carbamoyl]phenethyl]carbamoyl]-l-pyrrolidine-carboxylate; (2S.3S.5S)-2-(Boc-D-Pro-Phe-His-NH)-l-cyclohexyl-5--isopropyl-6-hepten-3-ol; N- (S)-[(1S,2S,4S)-1-(cyclohexylmethyl-2-hydroxy-4-iso-propyl-5-hexenyl]-a-[(S)-a-3-methylbutyramido]-imidazole-4-propionamide; t-butyl [(S)-a-[[(S)-l-[[(IS.2S.4S)-l-cyclohexyl-methyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazo1-4-ylethy1]carbamoyl]phenethyl] carbamate; t-butyl [(S)-a-[[(S)-l-[[(IS.2S.4S)-l-cyclohexyl-methyl-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol--4-ylethy1]carbamoyl]phenethyl] carbamate; t-butyl (S)-2-[[(R)-a-[[(S)-l-[[(lS.2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2--imidazo1-4-ylethy1]carbamoyl]phenethyl]acetyl]-1--pyrrolidinecarboxylate; 226395 - 14 - 10 15 20 25 30 35 "2 /NOV/99/71 (S)-N-[(1S.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[[[[(R)-a-2-hydroxy-l-(hydroxy-methyl)-l-methylethy1]carbamoyl]methyl]hydro-cinnamamido]imidazole-4-propionamide; N-[(S)-l-r[ (IS. 2S,4S)-l-cyclohexylmethyl)-2-hydroxy-4- -isopropylhexyl]carbamoylJ-2-imidazo1-4-ylethyl]-Y- -oxo-a-(1-naphthylmethyl)-4-morpholinebutyramide; N-(t-butoxycarbonyl)-[2-[(R and S)-3-[[(S)-l-[[(lS,2S,4S)- -1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]- carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-4-phenyl- butyramido]ethyl]glycine t-butyl ester; (S)-N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4- -isopropyl-5-hexenyl]-a-[(R)-a-[[[2-hydroxy-l- -(hydroxymethyl)-l-methylethyl]carbamoyl]methyl]- hydrocinnamamido]imidazole-4-propionamide; (S)-a-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanamido]-N- -[(IS,2S.4S)-l-(cyclohexylmethyl-2-hydroxy-4-isopropyl- -5-hexenyl]imidazole-4-propionamide; (S)-N-[(IS.2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4- -isopropyl-5-hexenyl]-a-2-[N-(morpholinocarbamoyl)-3- -phenyl-L-alanyl]amino]imidazole-4-propionamide; (S)-a-[(R)-a-(car bamoylmethyl)hydroc innamamido]-N- -[(IS.2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl- -5-hexenyl]imidazole-4-propionamide; (S)-N-[(IS,2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4- -isopropyl-5-hexenyl]-a-[(R)-a-[(dimethylcarbamoyl)- methyl]hydrocinnamamido]imidazole-4-propionamide; (S)-N-[(IS.2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4- -isopropyl-5-hexenyl]-a-[(RS)-a-[(cyclopentyl- carbonyl)methyl]hydrocinnamamido]imidazole-4-propion- amide; (S)-N-[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[(RS)-a-[(cyclopentylcarbonyl)-methyl]hydrocinnamamido]imidazole-4-propionamide and (2S,5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-l-cyclohexyl-5--isopropyl-6-hepten-3-ol. - 15 - 226395 The compounds of formula I in the form of optically pure diastereomers. diastereomer mixtures, diastereomeric racemates or mixtures of diastereomeric racemates as well as pharmaceutically usable salts thereof can be manufactured by a) for the manufacture of a compound of formula I in which A signifies the group (a) or (b) given above and the remaining symbols have the significance given above, reacting the compound of the general formula f 9 ?3 R" H i B i i v Aa k ch ch 3 3 II 12 3 4 wherein R , R . R and R have the significance given above. with an acylating agent yielding the group R5 J R \ .y \ / -Y-Z 5 (a) or (b) wherein R5, R6, Y. Z and the dotted line have the significance given above, or b) reacting a compound of the general formula / \ / N / i" A ch3 ch3 III /A/OV/99; £ ! V ^ 22 6 3 - 16 - wherein R3 and R4 have the significance given above, with a compound of the general formula 10 30 A A°« A 1 IV 'V 1 2 wherein R . R and A have the significance given above, or an activated derivative thereof, or 15 c) for the manufacture of a compound of formula I in 4 which R signifies ethyl and the remaining symbols have the significance given above, hydrogenating a compound of 4 formula I in which R signifies vinyl and the remaining symbols have the significance given above, or 20 d) for the manufacture of a compound of formula I in 4 which R signifies 1.2-dihydroxyethyl and the remaining symbols have the significance given above, oxidizing a 4 compound of formula I in which R signifies vinyl and 25 the remaining symbols have the significance given above, o e) for the manufacture of a compound of formula I in which A contains a free amino group, cleaving off the N-protecting group from a corresponding compound of formula I in which A contains a N-protected amino group, and/or 35 f) if desired, separating a mixture of diastereomeric racemates into the diastereomeric racemates or optically pure diastereomers, and/or 220395 - 17 - g) if desired, separating a diastereomer mixture into the optically pure dia6tereomers, and/or h) if desired, converting a compound obtained into a pharmaceutically usable salt. 10 The acylation of a compound of formula II is effected according to methods known per se. Especially suitable acylating agents are activated acid derivatives such as esters, mixed esters, acid halides and acid anhydrides or mixed anhydrides. The reaction is carried out in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about 0°C 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 20 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 such as HBTU (O-benzotriazolyl-25 -N.N.N'.N'-tetramethyluronium hexafluorophosphate). BOP (benzotriazol-l-yloxy bis-(dimethylamino)phosphonium hexa-fluorophosphate), HOBT (N-hydroxybenzotriazole), DBU (1.8--diazabicyclo[5.4.0]undec-7-ene). DCC (dicyclohexyl-carbodiimide). EDC (N-ethyl-N1 (3-dimethylaminopropyl)-30 carbodiimide hydrochloride), Hiinig base (ethyldiisopropyl-amine). and the like. The reaction is conveniently carried out in an organic solvent or solvent mixture which is inert'under the reaction conditions at a temperature between about 0° and 50°C, preferably at about room 35 temperature. As solvents there come into consideration especially dimethylformamide. methylene chloride, aceto-nitrile. tetrahydrofuran. and the like. 22 6 3 9 5 - 18 - 10 15 The reaction of a compound of formula III with 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 hydrogenation of a compound of formula I in which 4 R signifies vinyl is also effected according to methods known per se in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about room temperature and 50°C, preferably at "room temperature, in the presence of a noble metal catalyst such as platinum or palladium, preferably palladium. As solvents there come into consideration especially alcohols such as methanol or ethanol, and the like. 4 The oxidation of a compound of formula I in which R signifies vinyl is also effected according to methods known per se in an organic solvent or solvent mixture which is inert under the reaction conditions at a temper-25 ature between about room temperature and the boiling point of the solvent or solvent mixture, preferably at about room temperature. Osmium tetroxide is the especially suitable oxidizing agent. As solvents there come into consideration especially pyridine and the like. 30 The cleavage of the N-protecting group in accordance with process variant e) is also effected according to methods known per se in an organic solvent or solvent mixture which is inert under the reaction conditions at a 35 temperature between about 0°C and room temperature with an acid such as hydrochloric acid, trifluoroacetic acid, and 20 22G3!)r> I - 19 - the like. Suitable solvents are ethers such as tetrahydrofuran or dioxan, alcohols such as methanol or chlorinated 5 hydrocarbons such as methylene chloride, and the like. 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 10 optionally N-methylated histidine, norleucine or norvaline. This reaction is also effected according to methods which are known in peptide chemistry, i.e. under the reaction conditions described above for the reaction of a compound of formula II with a peptide. 15 20 The starting materials of formula III are also novel. They can be prepared, for example, by reacting an aldehyde of the general formula ?3 B-HN/ XCHO 25 30 35 wherein B signifies an amino protecting group, preferably t-butoxycarbonyl or benzyloxycarbonyl. and 3 R has the significance given above. with a compound of the general formula • R41 Y/ \ /K x T I VI / \ ch3 ch3 wherein X signifies chlorine, bromine or iodine. 0;\ 41 preferably bromine, and R signifies phenyl, furyl •'2 1 OCT 1991 -;i or vinyl. ' (TJ 22C>3<) - 20 - in a Grignard reaction. This reaction is also effected according to methods known per se. for example in a solvent which is inert under the reaction conditions, such as an ether, at a temperature between about 0° and 50°C, preferably at room temperature. Subsequently, the amino protecting group B is cleaved off from the obtained compound according to known methods, e.g. with hydrochloric acid in dioxan at room temperature. Where a 4 compound of formula III in which R signifies ethyl or 1,2-dihydroxyethyl is desired, the product of the Grignard reaction is hydrogenated or oxidized according to known methods prior to the cleavage of the amino protecting group B under the reaction conditions given for process variant c). Suitable oxidizing agents are osmium tetroxide, potassium permanganate, ruthenium tetroxide, and the like. The reaction is carried out in an organic solvent or solvent mixture which is inert under the reaction conditions at a temperature between about room temperature and 50°C. Suitable solvents are pyridine, aromatic hydrocarbons such as benzene, and the like. The compounds of formula V are known or can be obtained in analogy to the preparation of the known compounds. 41. The compound of formula VI in which R signifies 41 vinyl is known. The compounds of formula VI in which R signifies phenyl or furyl are novel. A process for the preparation of a compound of 4 . . . . formula III in which R signifies phenyl, furyl or vinyl is sketched in each of Schemes I-III hereinafter. The preparation of the novel compounds of formula VI in which 41 ?R signifies phenyl or furyl can also be concluded from 22 6 39 5 - 21 - Schemes II and III. With respect to the precise reaction conditions, reference is made to the experimental section. 226395 - 22 - Scheme I 10 25 • ] -0-C0-NH-(j:H-C00CH3 II I n-'" vii • J -0-C0-NH-(j:H-C00CH3 / \ / • • I I • • \ / VIII 15 20 | -0-C0-NH-(j!H-CH0 • • / \ / • • I I • • \ / Va + Br / \%/ ^ 1 / \ Via 30 35 / \ ?/ \ / I j-o' H Ah A I IX H2N / \ j I /e\ /* 0 © 1 ° • o / \ / \ / ^ a a Ah ^ Ilia 22 6 3 9 5 - 23 - 10 15 20 25 ch3ooc/ x hoch \ / I l ] ii %/• XIII J Br-CH2 VI b \ / I / \ S \ T i! % /* Scheme II \ / c^oC y xr, o • XI I hooc \ / I • .O / \ ^ \ • ® I II XII |-o-co-nh-(j:h-cho Vb \ / 1 30 i h ?« y i~°\ /N\ /*\ /"\ f'\ c • • • • 6 i J / \ xiv 35 ?h Y h n • * * * 2 \ / \ / \ ? \ / / V !v » 111 b 22 6 3 9 5 - 24 - Scheme III h3co / X,/ \cH. v /COOC2H5 V V' \ cooc2h5 XV 10 < )-n./c°2h N0/ 1 (rac) XVIII 15 V y*~Y v 20 \ /c02h ! (s) / \ XVI >-v °L- \ / 0' ./ V • XX ft XVII y v \ /C°2H i (R) / \ > v Y(;°« /VS) XlXa XlXb XXb 25 \ '0' 1 V/ N / \ oh (R) 30 XXa / Y V \ / \_. 35 n/ ] c1 / \ Vic -•-O-CO-NH-CH-CHO 1 / / \ Vc 10 - 25 - Scheme III (continued) 15 •y* .'"x. . sl ? \ / \ / \ / \ i t i n n0-j /*N OH H I XXI 20 v \ / I / V N. • • °V / \ / N / N NH V ;!n i„ HH2 IIIc 25 30 35 22 6 3 9 5 - 26 - The compounds of formula I and their pharmaceutically usable salts have an inhibitory activity on the natural 5 enzyme renin. The latter passes from the kidneys into the blood and there brings about the cleavage of angiotensinogen with the formation of the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to the octapeptide angiotensin II. Angiotensin II increases the blood pressure not only directly by 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 15 fluid volume. This increase is attributed to the action of angiotensin II itself or to 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 20 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. 25 The activity of renin inhibitors can be demonstrated experimentally by means of the in vitro test described hereinafter: 30 In vitro test with pure human renin The test is carried out in Eppendorf test tubes. The incubation mixture consists of (1) 100 ill of human renin in buffer A (0.1M sodium phosphate solution, pH 7.4. containing 0.1% bovine serum albumin. 0.1% sodium azide and 1 mM ethylenediaminetetraacetic acid), sufficient for 35 a renin activity of 2-3 ng of angiotensin I/ml/hr.; (2) 145 ill of buffer A; (3) 30 ill of 10 vM human tetra-decapeptide renin substrate (hTD) in 10 mM hydrochloric 22 6 3 9 5 - 27 - acid; (4) 15 vl of dimethyl sulphoxide with or without inhibitor and (5) 10 ul of a 0.03 molar solution of 5 hydroxyquinoline sulphate in water. The samples are incubated for 3 hours at 37°C or 4°C in triplicate. 2 x 100 ul samples per experimental test tube are used in order to measure the production of 1° angiotensin I via RIA (standard radioimmunoassay; clinical assay solid phase kit). Cross reactivities of the antibody used in the RIA are: angiotensin I 100%; angiotensin II 0.0013%; hTD (angiotensin I-Val-Ile-His-Ser-OH) 0.09%. The production of angiotensin I in determined by the 15 difference between the experiment at 37°C and that at 4°C. The following controls are carried out: (a) Incubation of hTD samples without renin and without 20 inhibitor at 37°C and 4°C. The difference between these two values gives the base value of angiotensin I production. (b) Incubation of hTD samples with renin, but without 25 inhibitor at 37°C and 4°C. The difference between these values gives the maximal value of angiotensin I production. In each sample the base value of the angiotensin I production is subtracted from the angiotensin I production 30 which is determined. 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 values which denote 35 that concentration of the inhibitor at which the enzymatic activity is inhibited by 50%. The IC5Q values are determined from a linear regression curve from a logit-log plot. 226395 10 15 - 28 - The results obtained in this test are compiled in the following Table: Table Compound IC50 values *n vMol/lt. A 0.0035 B 0.0003 C 0.0090 D 0.0075 E 0.0079 F 0.0040 G 0.0150 H 0.0041 I 0.0460 K 0.0170 L 0.0070 M 0.0210 N 0.1400 O 0.0120 P 0.0460 25 q 0.0680 R 0.0017 A= t-Butyl (R)-2-[[(S)-a-[[(S)-1-[(1S.2S.4S)-1-cyclohexy lme thy l-2-hydroxy-4- isopropylhexyl ]-2-imidazo1-4-yl-30 -ethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidine- carboxylate; B= (2S.3S.5S)-2-(Boc-D-Pro-Phe-His-NH)-l-cyclohexyl-5--isopropyl-6-hepten-3-ol; 20 35 N- (S)-[(IS.2S.4S)-1-(eyelohexylmethyl-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(S)-a-3-methylbutyramido]~ imidazole-4-propionamide; 226395 - 29 - t-butyl [(S)-a-[[(S)-l-[[(lS,2S,4S)-l-cyclohexyl-methyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazo1-4-ylethyl]carbamoyl]phenethyl] carbamate: t-butyl [ (S)-a-[[ (S)-l-[ [ (lS,2S,4S)-l-cyclohexyl- methyl-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazo1- -4-ylethyl]carbamoyl]phenethyl] carbamate; t-butyl (S)-2-[[(R)-a-t[(S)-1-[[(IS.2S.4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropylhexyl]carbamoyl]-2--imidazo1-4-ylethyl]carbamoyl]phenethyl]acetyl]-1--pyrrolidinecarboxylate; (S)-N-[(IS,2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[[[[(R)-a-2-hydroxy-l-(hydroxy-methyl)-1-methylethyl]carbamoyl]methyl]hydrocinnamamido ]imidazole-4-propionamide; N-(S)-l-[[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]-Y--oxo-a-(1-naphthylmethy1)-4-morpholinebutyramide; N-(t-butoxycarbonyl)-[2-[R and S)-3-[[(S)-1--[[(lS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]-4-phenylbutyramido]ethyl]glycine t-butyl ester; (S)-N-[(IS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(R)-a-[[[2-hydroxy-l--(hydroxymethyl)-l-methylethyl]carbamoyl]methyl]hydrocinnamamido] imidazole-4-propionamide; (S)-a-[(R)-2-benzyl-5.5-dimethyl-4-oxohexanamido]-N--[(IS.2S,4S)-1-(eyelohexylmethyl-2-hydroxy-4-isopropy1--5-hexenyl]imidazole-4-propionamide; 22 6 39 - 30 - M= (S)-N-[(IS,2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexeny1]-a-2-[N-(morpholinocarbamoyl)-3--phenyl-L-alanyl]amino]imidazole-4-propionamide; 10 N= (S)-a-[(R)-a-(carbamoylmethyl)hydrocinnamamido]-N- -[(IS,2S.4S)-l-(eyelohexylmethyl)-2-hydroxy-4-isopropyl--5-hexenyl]imidazole-4-propionamide; 0= (S)-N-[(is,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(R)-a-f(dimethylcarbamoyl)-methyl]hydrocinnamamido]imidazole-4-propionamide; 15 P= (S)-N-[(lS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(RS)-a-[(cyclopentyl-carbonyl)methyl]hydrocinnamamido]imidazole-4-propionamide; 20 Q= (S)-N-[(IS,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[(RS)-a-[(cyclopentylcarbonyl)-methyl]hydrocinnamamido]imidazole-4-propionamide and R= (2S.5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-l-eyelohexy1-5-25 -isopropyl-6-hepten-3-ol. The compounds of formula 1 as well as their pharmaceutically usable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharma-30 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 suspensions, nasally, e.g. in the form of nasal sprays, or rectally, e.g. in the form of 35 suppositories. However, the administration can also be effected parenterally such as intramuscularly or intravenously, e.g. in the form of injection solutions. 22 6 3 9 5 - 31 - For the manufacture of tablets, coated tablets. dragees and hard gelatine capsules the compounds of 5 formula I as well as their pharmaceutically usable salts can be processed with pharmaceutically inert, inorganic or organic excipients. Lactose, maize starch or derivatives thereof, 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. 15 Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. 20 Suitable excipients for injection solutions are e.g. water, alcohols, polyols. glycerol, vegetable oils etc. Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid 25 polyols etc. Moreover, the pharmaceutical preparations can contain preserving agents, solubilizers. viscosity-increasing substances, stabilizing agents, wetting agents, 30 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. 35 In accordance with the invention the compounds of general formula I as well as their pharmaceutically usable salts can be used in the control or prevention of high - 32 - 2 2 6 39 5 blood pressure and cardiac insufficiency. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In 5 general, in the case of oral administration there should suffice a daily dosage of 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, 10 the upper limit just given can also be exceeded when this is found to be indicated. Usually, children receive half of the dosage of adults. The following Examples are intended to illustrate the ^5 present invention, but are not intended to be limiting in any manner. All temperatures are given in degrees Celsius. The following abbreviations for amino acids and amino acid derivatives are used: 20 25 H-His-OH = L-histidine H-Phe-OH = L-phenylalanine H-Phe—His-OH = N-[(S)-2-amino-3-phenyIpropyl] ■ -L-histidine H-Pro-OH = L-proline H-Ser-OH = L-serine H-Tyr-OH = L-tyrosine Further abbreviations: 2q Boc » t-butoxycarbonyl Bom = benzyloxymethyl IVA = isovaleryl OBz = benzyloxy OMe = methoxy 35 Pip = piperidinyl Fmoc * 9-fluorenylmethoxycarbonyl t-Bu = t-butyl 22 6 395 10 - 33 -Example 1 A mixture of 313 mg (1.18 mmol) of t-butoxycarbonyl-L--phenylalanine, 460 mg (1.18 mmol) of (S)-a-amino-N--[(IS.2S.4S)-1-(cyclohexylmethyl) -2-hydroxy-4-isopropyl--5-hexenyl]imidazole-4-propionamide, 0.15 ml (1.18 mmol) of 4-ethylmorpholine. 320 mg (2.36 mmol) of HOBT and 292 mg (1.42 mmol) of DCC in 20 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the separated precipitate is filtered off and the solvent is evaporated in a high vacuum. The residue is dissolved in ethyl acetate and then washed in succession with 2N sodium 15 bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution. After drying the organic solution over sodium sulphate the solvent is evaporated under reduced pressure and. for 20 purification, the residue (870 mg) is chromatographed on 30 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/ether yields 410 mg of t-butyl [(S)— 25 -a-[[(S)-l-[[(1S.2S.4S)-1-(cyclohexylmethyl) -2-hydroxy--4-isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl] carbamate, melting point 161°. The (S)-a-amino-N-[(IS.2S,4S)-l-(cyclohexylmethyl)-30 -2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide used as the starting material was prepared as follows: 315.3 g (1.28 mmol) of t-butoxycarbonyl-L-phenyl-alanine methyl ester are hydrogenated according to the 35 method of J. Boger et al. in J. Med. Chem.. 28, 1779 (1985) in the presence of 5% rhodium on aluminium oxide at room temperature and 440 kPa. whereby there are obtained 22 6 395 - 34 - 315.3 g of 2-t-butoxycarbonylamino-3-cyclohexylpropionic acid methyl ester as an oil which is used directly in the 5 next step. 750 ml (750 mmol) of a 20% solution of diisobutyl-aluminium hydride in hexane are added dropwise at -75°C in the course of 90 minutes to 85.61 g (300 mmol) of 10 2-t-butoxycarbonylamino-3-cyclohexylpropionic acid methyl ester in 1.2 1 of toluene. After completion of the addition the reaction mixture is stirred at -75° for a further 10 minutes. There are subsequently added dropwise in each case within 25 minutes at a temperature of -75° to 15 -70° firstly 70 ml of methanol and then 840 ml of saturated potassium sodium tartrate solution. The milky reaction solution, warmed slowly to room temperature, is thereafter extracted with ether and the extracts are dried and evaporated, whereby there are obtained 82 g of 20 2-t-butoxycarbonylamino-3-cyclohexylpropyl aldehyde as an oil which is used in the next step without further purification. A solution of 179.7 g (1.01 mol) of 4-bromo-3-25 -isopropyl-l-butene (which was prepared according to the method of R. G. Helmquist in Tetrahedron Letters. 2533 (1982)) in 900 ml of ether was added dropwise within 2.5 hours to 24.65 g of magnesium shavings in 300 ml of ether in an argon atmosphere and at a temperature between 30 30° and the reflux temperature of the solvent. After completion of the addition the reaction mixture is heated to reflux for 3.5 hours. To the reaction mixture, cooled to -60°C. is added dropwise within 75 minutes a solution of 82 g of 2-t-butoxycarbonylamino-3-cyclohexylpropyl 35 aldehyde in 900 ml of ether, whereby the temperature amounts to -60° to -70°. After completion of the addition the cooling bath is removed and the reaction mixture is 22 6 39 5 10 15 - 35 - eticred at room temperature for 21 hours under argon. The mixture is then cooled to 5° and 225 ml of a saturated ammonium chloride solution is added cautiously while stirring, whereby the temperature rises to 20°. The two phases are separated and the organic phase is dried over sodium sulphate and evaporated, whereby there are obtained 127.5 g of a yellow oil. Chromatographic separation of this oil on 2.5 kg of silica gel with methylene chloride which contains 2.5% ether as the eluting agent yields 33.9 g of (aS.BS)-B-t-butoxycarbonylamino-a-[(S)-2--isopropyl -3-butenyl]cyclohexanepropanol. 13.62 g of (aS,BS)-B-t-butoxycarbonylamino-a-[(R)-2-isopropyl-3--butenyl]cyclohexanepropanol as well as 35.5 g of a mixture of both of the above-named diastereomers in the form of oils. MS: 354 (M+H)+. 1.0 g (2.83 mmol) of (aS.BS)-B-t-butoxycarbonyl-20 amino-a-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol is dissolved in 20 ml of 2.2N hydrogen chloride in dioxan and stirred at room temperature for 2 hours. Thereafter, the reaction mixture is evaporated and treated twice in succession firstly with toluene and then again evaporated 25 to dryness. In this manner there is obtained thin-layer chromatographically pure (aS,BS)-B-amino-a-[(S)-2--isopropyl-3 -butenylJcyclohexanepropanol in the form of the hydrochloride which is used directly in the next step. 30 1.7 g (2.83 mmol) of N-a-N-im-Bis-Fmoc-L-histidine and 0.82 g (2.83 mmol) of (aS,BS)-fl-amino-a-[(S)-2--isopropyl-3-butenyl]cyclohexanepropanol hydrochloride in 20 ml of dimethylformamide are treated with 0.36 ml of 4-ethylmorpholine and 0.77 g of HOBT and cooled in an ice 35 bath. 0.7 g of DCC is added to the cooled solution and the mixture is stirred overnight under an argon atmosphere without removing the ice bath, whereby the reaction 226395 - 36 - mixture is allowed to warm slowly to room temperature. Thereafter, the separated precipitate is filtered off and ^ the filtrate is evaporated in a high vacuum. The residue is poured on to ice and 70 ml of a 2N sodium bicarbonate solution 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 10 solution, once with 70 ml of ice and 2N sodium bicarbonate solution and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product (2.31 g) obtained in this manner is stirred at room temperature for 3 hours in 3 ml of piperidine and 75 ml of methylene chloride. The mixture is then evaporated at about 30° and the residue is triturated with 60 ml of hexane, whereby there are obtained 1.44 g of a solid which is chromatographed over 120 g of silica gel with a 12:1:0.1 mixture of methylene chloride, methanol 20 and ammonia. Two-fold recrystallization of the crude product obtained from hexane yields 580 mg of thin-layer chromatographically pure (S)-a-amino-N-[(IS.2S.4S)-1--(cyclohexylmethyl) -2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide as crystals, melting point 73°. 25 Example 2 130 mg (0.24 mmol) of t-butyl [(S)-a-[[(S)-l--[[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5-30 -hexeny1]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]- phenethyl] carbamate are dissolved in 30 ml of methanol and hydrogenated at room temperature for 1.5 hours in the presence of 65 mg of palladium-on-carbon (5%). After completion of the hydrogen uptake the catalyst is filtered 35 off and the filtrate is evaporated. Crystallization of the residue from ether/hexane yields 110 mg of t-butyl [(S)-a-[[(S)-l-[[(IS.2S.4S)-1-(eyelohexylmethyl)-2- £26395 10 - 37 - -hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyljphenethyl] carbamate as crystals, melting point 101°. Example 3 A mixture of 83 mg (0.345 mmol) of dibenzylacetic acid, 90 mg (0.23 mmol) of (S)-a-amino-N-[(lS.2S.4S)-l--(cyclohexylmethyl)-2 -hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. 0.045 ml (0.345 mmol) of 4-ethylmorpholine. 93 mg (0.69 mmol) of HOBT and 85 mg (0.41 mmol) of DCC in 15 ml of dimethylformamide is 15 stirred at room temperature overnight. Thereafter, the separated precipitate is filtered off and the filtrate is evaporated to dryness. The residue is then dissolved in ethyl acetate and the solution is washed in succession with 2N sodium bicarbonate solution, saturated ammonium 20 chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution, dried over sodium sulphate and evaporated. The thus-obtained residue is chromatographed on 30 g of silica gel with a 14:1:0.1 mixture of methylene chloride. 25 methanol and ammonia. Crystallization of the residue from methylene chloride/methanol/hexane yields 60 mg of (S)-N--t(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy -4-isopropyl--5-hexenyl]-a-(2,2-dibenzylacetamido)imidazole-4-propionamide, melting point 98°. 30 Example 4 A mixture of 880 mg (2.5 mmol) of (S)-a-amino-N--[(IS,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-35 imidazole-4-propionamide, 1.99 g (7.5 mmol) of t-butoxy-carbonyl-L-phenylalanine, 1.05 ml (7.5 mmol) of triethyl-amine and 3.32 g (7.5 mmol) of BOP in 100 ml of aceto- 2Z t) 3 9 5 10 15 - 38 - nitrile is stirred at room temperature for 6 days. Thereafter, the solvent is evaporated and the residue is dissolved in ethyl acetate and washed in succession with 2N sodium bicarbonate solution, saturated ammonium chloride solution, again with 2N sodium bicarbonate solution and again with saturated ammonium chloride solution. The organic solution is dried over sodium sulphate and evaporated and the residue is triturated twice with hexane. The residue is chromatographed on 100 g of silica gel with a 98:2 mixture of chloroform and methanol. Recrystallization of the thus-obtained crude product from methylene chloride and hexane yields 400 mg of t-butyl [(S)-a-[[(S)-l-[[(1S.2S.4S)-2-hydroxy-l--isobutyl-4 -isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4--ylethyl]carbamoyl]phenethyl] carbamate as a white powder, melting point 82°. The (S)-a-amino-N-[(IS.2S.4S)-2-hydroxy-1-isobuty1--4-isopropyl-5-hexenyl]imidazole-4-propionamide used as the starting material was prepared as follows: t-Butoxycarbonyl-L-leucine methyl ester is reduced 25 with diisobutylaluminium hydride in an analogous manner to that described in Example 1 to give 2-t-butoxycarbonyl-amino-4-methyl-valeraldehyde which is used directly in the next step without further purification. 30 A solution of 142.3 g (691 mmol) of 4-bromo-3-iso- propyl-l-butene in 600 ml of ether is added dropwise within 75 minutes to 16.8 g of magnesium shavings in 980 ml of ether under argonand at room temperature. After completion of the addition the reaction mixture is heated 35 to reflux for 3.25 hours and thereafter cooled to -60°. Thereto there is added dropwise within 75 minutes a solution of 50.1 g (203.8 mmol) of 2-t-butoxycarbonyl- 20 22 6 3 9 5 10 15 - 39 - amino-4-methyl-valeraldehyde in 600 ml of ether. After completion of the addition the cooling bath is removed and, the reaction mixture is stirred at room temperature for 17 hours. The mixture is then cooled to 5° and 150 ml of a saturated ammonium chloride solution are added dropwise thereto while stirring, whereby the temperature rises to 20°. After analogous working-up to that described in Example 1 there are obtained 88.4 g of a yellow oil which is chromatographed on 2.5 kg of silica gel with a 98:2 mixture of methylene chloride and ether. After repeated chromatgraphy of the mixed fractions under the same conditions there are obtained a total of 30.2 g of pure, thin-layer chromatographically uniform (4S)-t-butoxy-carbonylamino-(5S)-hydroxy-(7S) -isopropyl-2-methy1-8--nonene, MS: 240 (M-t-butoxy)+. The t-butoxycarbonyl group is cleaved off with hydrogen chloride in dioxan in an analogous manner to that described in Example 1 and the thus-obtained (4S)-amino-(5S)-hydroxy-(7S)-isopropyl-2-methyl-8-nonene is used directly in the next step without further purification. 25 a mixture of 550 mg (1.75 mmol) of (4S)-amino(5S)- -hydroxy-(7S)-isopropyl-2-methyl-8-nonene. 1.547 mg (2.65 mmol) of N-a-N-im-Bis-Fmoc-L-histidine. 2.323 g of BOP and 0.73 ml of triethylamine in 30 ml of acetonitrile is stirred at room temperature for 4 days. Thereafter, the solvent is evaporated under reduced pressure and the residue is worked-up in an analogous manner to that described in Example 1. Chromatography of the crude product on 500 g of silica gel with a 140:5:0.5 mixture of methylene chloride, methanol and ammonia yields 950 mg of 35 fluoren-9-ylmethyl [(S)-l-t[(1S.2S.4S)-2-hydroxy-l- -isobuty1-4-isopropyl -5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl] carbamate as an oil which is used directly in the next step. MS: 369 (M+H)+. 20 30 226395 - 40 - 1.3 g of fluoren-9-ylmethyl [(S)-l-[[(lS,2S,4S)-2--hydroxy-1-isobuty1-4-isopropyl-5-hexenyl]carbamoyl]-2-5 -imidazol-4-ylethyl] carbamate in 30 ml of methylene chloride and 2 ml of piperidine are stirred at room temperature for 1.5 hours. Thereafter, the solvent is evaporated and the residue is triturated with hexane. The (S)-a-amino-N-[(IS.2S.4S)-2-hydroxy-1-isobuty1-4-iso-propyl-5-hexenyl]-imidazole-4-propionamide obtained in this manner is used in the next step without further purification. Example 5 15 A mixture of 460 mg (1.18 mmol) of (S)-a-amino-N--[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]imidazole-4-propionamide. 313 mg (1.18 mmol) of t-butoxycarbonyl-L-phenylalanine. 0.15 ml (1.18 mmol) of 20 4-ethylmorpholine. 320 mg (2.36 mmol) of HOBT and 292 mg (1.42 mmol) of DCC in 20 ml of dimethylformamide is stirred at room temperature for 18 hours and subsequently worked-up in the usual manner. Chromatography of the residue on 30 g of silica gel using a 20:1:0.1 mixture of 25 methylene chloride, methanol and ammonia as the eluting agent yields 410 mg of crystals of melting point 161°. 2.5 g of the above compound are dissolved in 50 ml of 2.2N hydrogen chloride in dioxan and stirred at room 30 temperature for 6 hours. Thereafter, the reaction mixture is evaporated under reduced pressure and the residue is purified by chromatography on silica gel with a 190:10:1 mixture of methylene chloride, methanol and ammonia, whereby there is obtained N-[(lS.2S,4S)-l-(cyclohexyl-35 methyl)-2-hydroxy-4 -isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide as a uniform material, MS: 538 (M+H)+. 22 6 3 9 5 - 41 -Example 6 The following compounds were manufactured in an analogous manner to that described in Example 1: - from (S)-a-amino-N-t(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and a-benzyltetrahydro-0-oxo--4H-1.4-oxazinepropionic acid the (S)-N- -[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(RS)-a-(morpholino-car bony1)hydrocinnamamido]imidazole-4-propionamide as crystals of melting point 94° (from methylene chloride/ether/hexane); - from (S)-a-amino-N-[(IS,2S,4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and t-butoxycarbonyl-D-proline the (2S.3S.5S)-2-(Boc-D-Pro-Phe-His-NH)-l-cyclo-hexyl-5-isopropyl-6-hepten-3-ol as crystals of melting point 132° (from methylene chloride/ ether/hexane); - from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propianamide and t-butyl-acetic acid the (S)-N-[(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]-a-[(S)--a-(3.3-dimethylbutyramido)hydroc innamoyl]-imidazole-4-propionamide as crystals of melting point 105° (dec.; from methylene chloride/ether/ hexane); - from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and isovaleric acid the N-(S)-[(lS.2S,4S)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-3- 226395 10 15 - 42 - -methylbutyramido]imidazole-4-propionamide as a foam. MS: 622 (M+H)+; - from (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl3 imidazole--4-propionamide and (S)-a-[[(S)-2-benzylamino--3-phenylpropyl3amino3hydrocinnamic acid the benzyl [a-[[[a-[[(S)-l-[[(IS.2S,4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl3 carbamoyl]-phenethyl]amino]methyl]phenethyl]carbamate as crystals of melting point 89° (from methylene chloride/ether/hexane); - from (S)-a-amino-N-[(s)-l-[[(IS.2S.4S)-2--hydroxy-1-isobuty1-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethy1]hydrocinnamamide, which was obtained from t-butyl [(S)-a-[[(S)-l--[[(IS.2S,4S)-2-hydroxy-1-isobuty1-4-isopropyl-5--hexenyl]carbamoyl]-2-imidazole-4-ylethyl]-carbamoyl]-phenethyl] carbamate by leaving to stand at room temperature for 18 hours in 0.3N methanolic hydrochloric acid, and cyclopentane-carboxylic acid the (S)-a-[(RS)-cyclopentane- 25 carboxamido]-N-[(S)-1-[[(1S.2S.4S)-2-hydroxy-l- -isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazol-4-ylethyl]hydrocinnamamide as crystals of melting point 185° (dec.; from methanol/ methylene chloride/hexane); 30 - from N-[(lS.2S,4S)-l-(cyclohexylmethyl)-2- -hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propianamide and benzyl [(methylthio)formimidoyl] carbamate1 the benzyl [N-[(S)-a-[[(S)-l-[[(lS.2S,4S)-l-(cyclohexyl-35 methyl)-2-hydroxy—4-isopropyl-5-hexenyl3- carbamoyl3-2-imidazo1-4-ylethyl3carbamoyl]-phenethyl3amidino3 carbamate as a foam. MS: 714 (M+H)+; 20 1 GB Patent Specification 2.085.444 22 6 3 9 5 10 - 43 - - from N-[(IS,2S,4S)-1-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propianamide and t-butoxy-carbonylaminovaleric acid the t-butyl [4[[(S)~ -a-[[(S)-l-[[(IS,2S,4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-butyl] carbamate as crystals of melting point 110° (from methylene chloride/ether/hexane); - from (S)-a-amino-N-[(IS,2S,4S)-1-(eyelohexy1- methyl)-2-hydroxy^4-isopropyl-5-hexenyl]imidazole--4-propionamide and N-t-butoxycarbonyl-N-methyl-l5 -L-phenylalanine the t-butyl [(S)-a-t[(S)-l- -(S)- -[[(lS,2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazo1-4-ylethy1]carbamoyl]phenethyl]methyl carbamate as crystals of melting point 93° (from ether/hexane); - from (S)-a-amino-N-[(IS,2S,4R)-1-(cyclohexylmethyl ) -2-hydr oxy-4 -isopr opyl- 5-hexenyl ]imidazole--4-propionamide and t-butoxycarbonyl-L-phenyl-alanine the (2S.3S.5R)-2-(Boc-Phe-His-NH)-l- 25 -cyclohexyl-5-isopropyl-6-hepten-3-ol as a foam, MS; 638 (M+H)+; - from (S)-a-amino-N-[(lS,2S,4S)-l-(cyclohexyl- methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole- 2 -4-propionamide and dibenzsuberaneacetic acid the N-[(lS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy--4-isopropyl-5-hexenyl]-a-[2-(10,11-dihydro--5H-dibenzo[a,d]cyclohepten-5-yl)acetamido]-imidazole-4-propionamide as crystals of melting point 135° (from methylene chloride/ether/hexane); 35 _ from (S)-a-amino-N-[(lS,2S,4S)-l-(cyclohexyl- methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and 3-(3-indolyl)propionic acid 2 EPA 0.056.616 22 6 3 9 5 10 15 - 44 - the (S)-N-[(lS,2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-indol-3--ylpropionamido)imidazole-4-propionamide as a solid of melting point 122° (from ether/hexane); - from (S)-a-amino-N-t(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and benzylmalonic acid monoamide the (S)-a-[(RS)-a-carbamoylhydrocinnamamido]--N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide as a foam. MS: 566 (M+H)+; - from (S)-a-amino-N-t(IS.2S.4S)-1-(cyclohexylmethyl) -2-hydr oxy-4- isopr opyl- 5-hexenyl] imidazole--4-propionamide and (S)-a-benzyl-2.5-dimethyl-pyrrol-l-acetic acid the (S)-N-[(1S.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-[(S)-a-(2.5-dimethylpyrrol-l-yl)-hydrocinnamamido]imidazole-4-propionamide as crystals of melting point 93° (from ether/hexane): - from (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl- methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and a-[(2-hydroxyethyl)-25 carbamoyl]hydrocinnamic acid the (S)-N- -[(IS. 2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(RS)-a-[(2-hydroxy-ethyl)carbamoyl]hydrocinnamamido]imidazole-4--propionamide as a foam. MS: 610 (M+H)+; - from (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl- methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and a-[[2-(dimethylamino)-ethyl]carbamoyl]hydrocinnamic acid the (S)-N--[(IS.2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4-35 -isopropyl-5-hexenyl-a-[(RS)-a-[[2-(dimethyl- amino)ethyl]carbamoyl]hydrocinnamamido]imidazole-4--propionamide as a foam, MS: 637 (M+H)+; 20 30 22 6 3 9 - 45 - from (S)-a-amino-N-[(IS.2S,4S)-1-(eyelohexy1-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and dibenzyl-cyanoacetic acid the (S)-a-(a-benzyl-a-cyanohydt ocinnamamido)-N--[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide as crystals of melting point 105° (from ether/ hexane); from (S)-a-amino-N-f(lS,2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and benzyl-cyanoacetic acid the (RS)-a-cyarto-N-[(S)-1-[[(IS.2S.4S)-1-(eyelohexy1-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl] -2-imidazo1-4-ylethyl]hydrocinnamamide as crystals of melting point 97° (from methylene chloride/ether/hexane); from (S)-a-amino-N-f(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and indole-2-carboxylic acid the N-[(S)-l-[[(IS.2S.4S)-1-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazol-4-yl-ethyl]-2-benzimidazolecarboxamide as crystals of melting point 123° (from methylene chloride/ether/hexane); from (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and isovaleric acid the (S)-N--[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-(3-methylbutyramido)-imidazole-4-propionamide as a foam. MS: 622 (M+H) + ; from (S)-a-amino-N-[(IS.2S,4S)-1-(cyclohexylmethyl) -2-hydr oxy-4 -isopr opyl- 5-hexenyl ]imidazole--4-propionamide and a-benzyl-B-oxo-1--pyrrolidinepropionic acid the N-[(1S.2S.4S)-!- 226395 10 15 - 46 - -(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-[(RS)-a-(1-pyrrolid inylcarbonyl)-hydrocinnamamido]imidazole-4-propionamide as crystals of melting point 89° (from methylene chloride/ether/hexane); - from (S)-ct-amino-N-[(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and a-[(benzyloxy)carbamoyl]-hydrocinnamic acid the (S)-a-[(RS)-a--[(benzyloxy)carbamoyl]hydrocinnamamido]-N--[(IS,2S.4S)-l-cyclohexyl-2-hydroxy-4-isopropyl-5--hexenyl]imidazole-4-propionamide as crystals of melting point 104° (from methylene chloride/ ether/hexane); - from (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and 1-[a-(methoxycarbonyl)-hydrocinnamoyl]-4-piperidinecarboxylic acid the methyl (RS)-a-[[4-[[(S)-l-[[(IS.2S.4S)-1- -(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]piperidino]carbonyl]hydrocinnamate as 25 crystals of melting point 89° (from methylene chloride/ether/hexane). The acids used as starting materials are either known or were prepared as follows: 30 a-Benzyltetrahydro-fl-oxo-4H-l.4-oxazinepropionic acid benzylmalonic acid monomethyl ester, which in turn had been prepared according to known methods3, is amidated with morpholine according to usual methods and 35 subsequently hydrolyzed with IN sodium hydroxide solution to give a-benzyltetrahydro-fl-oxo-4H-l.4-oxazinepropionic acid. MS: 264 (M+H)+. 20 3 M. Goodman et al.. J. Am. chem. Soc.. 77. 8675 (1969) and Int. J. Pept. Prof. Res.. 21. 84 (1983) 22 6 3 9 5 - 47 - (S)-a-[[(S)-2-Benzylamino-3-phenylpropyl]amino]- hydrocinnamic acid In an analogous manner to the preparation of R 5 Boc-Phe-His(Bom)-OH described in Example 26. there was prepared [from] N-benzyl-Phe-Phe-OMe by sulphurization of the amide carbonyl group, desulphurization thereof with Raney-nickel and subsequent hydrolysis of the ester obtained the (S)-a-[[(S)-2-benzylamino-3-phenyl-propyl]amino]hydrocinnamic acid which is used directly in the next step. t-Butoxycarbonylaminovaleric acid 5-Aminovaleric acid is converted under Schotten-Baumann 25 conditions with di-t-butyl carbonate in the usual manner into the corresponding N-protected acid, melting point 48-50° (from ether/hexane). Benzylmalonic acid monoamide 20 Benzylmalonic acid monomethyl ester is amidated with ammonia in the usual manner and the 2-benzyl-2-formamido-acetic acid methyl ester obtained is hydrolyzed with IN sodium hydroxide solution in a 9:1 mixture of methanol and water within 30 minutes to benzylmalonic acid monoamide. Rf: 0.15 in a 90:10:1:0.5 mixture of chloroform, methanol, water and acetic acid. (S)-a-Benzyl-2.5-dimethylpyrrole-l-acetic acid L-Phenylalanyl methyl ester hydrochloride is converted into the corresponding free base by shaking with a sodium bicarbonate solution in ether and heated to 100° for 2.5 hours in glacial acetic acid with acetonylacetone. Thereafter, the solvent is evaporated and the residue is filtered with toluene over silica gel. whereby there is obtained methyl (S)-a-benzyl-2,5-dimethylpyrrole-l--acetate. MS: 258 (M+H)+. The ester obtained is left to 25 30 35 22 6 3 9 5 - 48 - stand at room temperature for 1.5 hours with IN sodium hydroxide solution in a 9:1 mixture of methanol and water. 5 After extracting the aqueous solution with ether and washing the organic phase there is obtained (S)-a--benzyl-2,5-dimethylpyrrole-l-acetic acid, MS: 244 (M+H)+, which is used directly in the next step. ^ a-T(2-Hydroxvethyl)carbamoyllhvdrocinnamic acid In an analogous manner to that described above for a-benzyltetrahydro-fl-oxo-4H-l,4-oxazinepropionic acid, benzylmalonic acid monoethyl ester is amidated with ^ ethanolamine and the compound obtained is saponified to a-[(2-hydroxyethyl)carbamoyl]hydrocinnamic acid. MS: 251 (M)+. which is used directly in the next step. a-T T2-(Dimethylamino)ethyl1 carbamoyl1hydrocinnamic acid 20 In an analogous manner to that described above for a-benzyltetrahydro-B-oxo-4H-l.4-oxazinepropionic acid, benzylmalonic acid monomethyl ester is amidated with N.N-dimethylaminoethylamine and subsequently saponified to <*-[ [ (2- (dime thy lamino) ethyl ] carbamoyl ] hydrocinnamic acid. [MS: 265 (M+H)+]. which is used directly in the next step. Dibenzyl-cyanoacetic acid 30 Cyanoacetic acid ethyl ester is dibenzylated in the presence of sodium ethylate with excess benzyl bromide in ethanol to give dibenzyl-cyanoacetic acid ethyl ester which is hydrolyzed with IN sodium hydroxide solution in a 35 9:1 mixture of methanol and water to give dibenzyl-cyanoacetic acid, melting point 194° (from methylene chloride/ methanol/hexane). 22 6 3 9 5 - 49 - Benzyl-cvanoacetic acid 5 Cyanoacetic acid ethyl ester is alkylated with benzyl bromide in the presence of sodium ethylate in ethanol to give benzyl-cyanoacetic acid ethyl ester IMS: 203 (M)+] which is then subsequently hydrolyzed with IN sodium hydroxide solution in a 9:1 mixture of methanol and water to give the corresponding acid. Recrystallization of the crude product from methylene chloride/hexane yields benzyl-cyanoacetic acid as crystals of melting point 97°. g-Benzvl-fl-oxo-l-pyrrolidinepropionic acid 15 In an analogous manner to that described for a-benzyl-tetrahydro-B-oxo-4H-l,4-oxazinepropionic acid, benzylmalonic acid monomethyl ester is amidated with pyrrolidine and the product obtained is hydrolyzed to a-benzyl-B-20 -oxo-l-pyrrolidinepropionic acid which is used directly in the next step, MS: 248 (M+H)+. a—T(Benzvloxy)carbamoyllhvdrocinnamic acid 25 In an analogous manner to that described for a-benzyl-tetrahydro-B-oxo-4H-l,4-oxazinepropionic acid, benzylmalonic acid monomethyl ester is amidated with O-benzyl-hydroxylamine and the resulting product [MS: 314 (M+H)+] is saponified with IN sodium hydroxide solution in a 9:1 30 mixture of methanol and water to the corresponding acid. Recrystallization of the crude product from methanol/ methylene chloride/ether yields a-[(benzyloxy)-carbamoyl]hydrocinnamic acid of melting point 147°. 35 22 6 3 9 5 - 50 - 1-Ta-(Methoxycarbonyl)hydrocinnamoyn-4-piperidine-carboxvlic acid 5 In an analogous manner to that described for the preparation of a-benzyltetrahydro-B-oxo-4H-l.4-oxazinepropionic acid, benzylmalonic acid monomethyl ester is amidated with piperidine-4-carboxylic acid ethyl ester and 10 the resulting compound [MS: 347 (M)+] is saponified with IN sodium hydroxide solution in a mixture of methanol and water at 0° for 2 hours. The crude product obtained is purified by chromatography on silica gel with a 95:5:2 mixture of chloroform, ethanol and ethyl acetate and 15 recrystallized from a mixture of methanol, methylene chloride and ether, whereby there is obtained l-[a--(methoxycarbony1)hydrocinnamoyl]-4-piperidinecarboxylic acid, melting point 138°. 20 Example 7 In an analogous manner to that described in Example 1. N-[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4-propiananide 25 is reacted with di-t-butoxycarbonyl-aminoethylglycine. Chromatographic purification and recrystallization of the crude product yields di-t-butyl N-[[[(S)-a-[[(S)-l--[[(IS.2S.4S)-1-(cyclohexylmethyl) -2-hydroxy-4-isopropyl--5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-30 phenylethyl]carbamoyl]methyl]ethylenedicarbamate. melting point 109°. 150 mg of N-[[[(S)-a-[[(S)-1-[[(1S.2S,4S)-1-(cyclohexylmethyl ) -2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-35 -2-imidazol-4-ylethyl]carbamoyl]phenylethyl]carbamoyl]-methyl]ethylenedicarbamate are dissolved in 0.3N hydrochloric acid in methanol and left to stand at room temperature overnight. Thereafter, the solvent is evaporated and the residue is precipitated from methanol/ethyl acetate, whereby there is obtained (S)-a-[(S)-a-[2-[(2-amino- 22 6 3 9 5 10 20 - 51 - ethy1)amino]acetamido]hydrocinnamido]-N-[(1S,2S,4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide trihydrochloride. MS: 638 (M+H)+. The di-t-butoxycarbonyl-aminoethylglycine used as the starting material was prepared as follows: N-(2-Aminoethyl)glycine is prepared according to the method described by E. P. Heimer in Int. J. Pept. Prot. Res., 23.. 203 (1984) and converted in a known manner under Schotten-Baumann conditions with di-t-butyl carbonate into the corresponding N-protected acid, MS: 319 (M+H)+. Example 8 60 mg of (2S.3S.5S)-2-(Boc-D-Pro-Phe-His-NH)-l-cyclohexy 1-5- isopr opyl-6-hept en- 3 -ol are dissolved in 10 ml of 2.IN hydrogen chloride in dioxan and stirred at room temperature for 1.5 hours. The solvent is then evaporated and the residue is treated twice in succession firstly with toluene and thereafter again evaporated to dryness. 25 Crystallization of the thus-obtained residue from methylene chloride/ether/hexane yields 40 mg of (S)-N--[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4 -isopropyl--5-hexenyl]-a-[(S)-a-(D-prolylamino)hydrocinnamamido]-imidazole-4-propionamide dihydrochloride as white crystals 30 of melting point 159°. Example 9 N-Methyl-L-histidine is converted with benzyl alcohol 35 in the presence of hydrochloric acid at room temperature into the corresponding benzyl ester and this is reacted according to the procedure described by D. H. Rich et al. 22 6 3 9 5 - 52 - in Proc. 9th American Pept. Symp.. Toronto 1985. page 217. with t-butoxycarbonyl-L-phenylalanine in the usual 5 manner. Thereafter, the N-[N-t-butoxycarbonyl)-3-phenyl-L--alanyl]-N-methyl -L-histidine benzyl ester obtained is hydrogenated for one hour in the presence of 5% palladium on carbon, whereby there is obtained N-[N-(t-butoxy-carbonyl)-3-phenyl-L-alanyl]-N-methyl -L-histidine, Rf: 0.2 in a 80:20:3:3 mixture of chloroform, methanol, water and acetic acid. This compound is then reacted in the usual manner with (aS.BS)-B-amino-a-[(S)-2-isopropyl--3-butenyl]cyclohexanepropanol. The crude product obtained is then chromatographed on silica gel with a 20:1:0.1 mixture of methylene chloride, methanol and ammonia, whereby the two epimeric compounds are separated. Recrystallization of the crude product obtained from the first fraction from ether/ methylene chloride/hexane yields t-butyl [(S)-a-[[(S)-l-[[(IS.2S.4S)-1-(cyclo-20 hexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]--2-imidazol-4-ylethyl]methylcarbamoyl]-phenylethyl] carbamate as white crystals of melting point 95°. From the second fraction there is obtained after 25 recrystallization from ether/methylene chloride/hexane the epimeric compound t-butyl [(S)-a-[[(R)-l-[[(1S.2S.4S)-1--(cyclohexylmethyl) -2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]methylcarbamoy1]phenethyl] carbamate as white crystals of melting point 85°. 30 In an analogous manner to that described above, N-t-butoxycarbonyl-N-methyl-L-phenylalanine is reacted with N-methyl-L-histidine benzyl ester according to the method described by Rich et al., the ester obtained is 35 subsequently hydrogenated to the corresponding acid and this is reacted in the usual manner with (aS.BS)-fl--amino-a-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol. 22 6 3 9 5 - 53 - 10 15 20 30 Chromatographic purification of the crude product on silica gel with a 140:1:0.1 mixture of methylene chloride, methanol and ammonia yields thin-layer chromato-graphically pure t-butyl [(S)-a-[[(S)-a-[[(1S.2S.4S)--l-(eyelohexylmethyl) -2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]methylcarbamoyl]phenethyl] methyl carbamate in the form of a foam. MS: 666 (M+H)+. Example 10 150 mg (0.20 mmol) of t-butyl 2-benzyl-2-[[(S)-1--[[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3--phenylpropyl] carbamate are dissolved in 10 ml of 0.3N methanolic hydrochloric acid and left to stand at room temperature overnight. Thereafter, the solvent is evaporated and. for purification, the residue is chromato-graphed on 30 g of silica gel with a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Recrystallization of the thus-obtained crude product from methylene chloride/ether/hexane yields (S)-a-(3-amino-2.2-dibenzylpropionamido)-N-[(IS.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide as white crystals of melting point 89®. The t-butyl 2-benzyl-2-[[(S)-l-[[(IS.2S.4S)-1-(cyclohexylmethyl ) -2-hydr oxy-4- isopr opyl- 5-hexenyl ] car bamoyl ] -2--imidazo1-4-ylethyl]carbamoyl]-3-phenylpropyl] carbamate used as the starting material was prepared as follows: Dibenzylcyanoacetic acid methyl ester is reduced with Raney-nickel in methanolic ammonia to dibenzylmethylamino-acetic acid ethyl ester [MS: 284 (M)+] which is then protected at the amino group with di-t-butyl carbonate in LL 6 - 54 - triethylamine in the usual mannec. The ester [MS: 398 (M+H)+] obtained in this manner is subsequently saponified with IN sodium hydroxide solution in a mixture of methanol and water to the corresponding acid which, after recrystallization from methanol/methylene chloride/ hexane. is isolated as crystals of melting point 157°. The acid is thereafter reacted in the usual manner with (S)-a-amino-N-[(IS,2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide to give t-butyl 2-benzyl-2-[[(S)-l-[[(IS,2S,4S)-1-(cyclohexylmethyl) -2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]--2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl] carbamate. Recrystallization from methylene chloride/ hexane/ether yields white crystals of melting point 97°. Example 11 150 mg of (S)-a-[(RS)-a-[(benzyloxy)carbamoyl]-hydrocinnamamido]-N-[(IS,2S.4S)-1-cyclohexy1-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide are hydrogenated in the presence of 5% palladium on carbon in methanol for 3 hours. After completion of the hydrogen uptake the catalyst is filtered and the filtrate is evaporated. Recrystallization of the residue from methanol/methylene chloride/ether yields (S)-N--[(IS,2S,4S)-1-(cyclohexylmethyl)-4-ethyl-2-hydroxy-5--methylhexyl]-a-[(RS)-a-(hydroxycarbamoyl)hydro-cinnamamido]imidazole-4-propionamide as white crystals of melting point 123°. Example 12 35 120 mg of t-butyl [(S)-a-[[(S)-l-(S)-[[(IS,2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoy1]-2-imidazo1-4-ylethyl]carbamoyl]phenethyl]methyl 22 6 3 9 - 55 - carbamate are dissolved in 0.3N methanolic hydrochloric acid and stirred at room temperature overnight. Thereafter, the solvent is evaporated under reduced pressure and the residue is treated with t-butylacetyl chloride and triethylamine in tetrahydrofuran and left to stand at room temperature overnight. After usual working-up, chromatographic purification on silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia and recrystallization from ether/hexane there is obtained (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4 -isopropyl-5-hexenyl]-a-[(S)-a-(N,3,3--trimethylbutyramido)hydrocinnamamido]imidazole-4-propionamide as white crystals of melting point 126°. Example 13 The following compounds were manufactured in an analogous manner to that described in Example 1: - From N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 3-(4-hydroxyphenyl)propionic acid the (S)-N--[(IS,2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(S)-o-(p-hydroxyhydro-cinnamamido) -hydrocinnamamido] imidazole-4-propion amide as white crystals, melting point 120° (from methylene chloride/ether/hexane); - from N-[(lS,2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and nicotinic acid the (S)-N-[(lS,2S,4S)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]-<x-[ (S)-a--nicotinamidohydrocinnamamido]imidazole-4-propion amide as a solid. MS: 643 (M+H)+; 25 30 35 22 6 3 9 5 - 56 - from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropy1-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 3-(4--pyridyl)acrylic acid the (S)-N-[(IS.2S.4S)-1--(cyclohexylmethyl)-2-hydcoxy-4-isopropyl-5--hexenyl]-a-[[(S)-a-[(E)-4-pyridineacrylamido]-hydrocinnamido]imidazole-4-propionamide as yellowish crystals, melting point 135° (dec.: from methylene chloride/ether/hexane): from N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 3-(3--pyridyl)acrylic acid the (S)-[(1S.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-[(S)-a-(3-pyridineacrylamido)-hydrocinnamamido]imidazole-4-propionamide as yellowish crystals, melting point 141° (from methylene chloride/ether); from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 3-(4--imidazolyl)acrylic acid (urocanic acid) the (S)-N-[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4 -isopropyl-5-hexenyl]-a-[(S)-a-(imidazo1-4--acrylamido)hydrocinnamamido]imidazole-4-propionamide as white crystals, melting point 150-152° (from methylene chloride/methanol/ether): from N-[(lS,2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and D-(-)-quinic acid the (S)-N-[(lS.2S,4S)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a--(1,3,4,5-tetrahydroxycyclohexanecarboxamido)hydro cinnamamido]imidazole-4-propionamide as a white solid. MS: 712 (M+H)+; iZ 6 3 9 5 - 57 - from N-[(IS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and quinaldic acid the N-[(S)-a-[[(S)-l-[[(IS.2S.4S)-1--(eyelohexylmethy1)-2-hydroxy-4-isopropyl-5--hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]-2-quinolinecarboxamide as a white solid. MS: 693 (M+H)+; from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and levulinic acid the (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(4--oxavaleramido)hydrocinnamamido]imidazole-4--propionamide as white crystals, melting point 150° (dec.; from methylene chloride/ether/hexane); from N-[(lS.2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 3-pyridyl-acetic acid the (S)-N-[(lS,2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]-a-[(S)--a-(3-pyridineacetamido)hydrocinnamamido]-imidazole-4-propionamide as white crystals. melting point 195° (dec.; from methanol/methylene chloride/hexane); from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropy1-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 4-chloro-cinnamic acid the (S)-N-[(IS.2S.4S)-l-(cyclohexy lmethyl )-2-hydroxy-4- isopropy 1-5-hexenyl ]--a[(S)-d-(4-chlorocinnamamido)hydrocinnamamido] imidazole-4-propionamide as white crystals, melting point 139° (from methylene chloride/ methanol/ether); 22 6 3 9 5 - 58 - from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropy1-5-hexeny1]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and trans-4--nitrocinnamic acid the (S)-N-[(1S.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-[(S)-a-(4-nitrocinnamamido)hydrocinnamamido] imidazole-4-propionamide as yellowish crystals, melting point 120° (dec.; from methylene chloride/methanol/ether); from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and fumaric acid monoethyl ester the ethyl 3-t[(S)-a-[[(S)-l--[[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethy1]carbamoy1]phenethyl]carbamoyl]aerylate as white crystals, melting point 175° (dec.; from methylene chloride/methanol/hexane); from (S)-a-amino-N-t(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and diphenylcarbamoyl-L-phenyl-alanine an epimeric mixture of (S)-N--[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[[N-(diphenylcarbamoyl)--3-phenyl-L-alanyl]amino]imidazole-4-propionamide and (S)-N-[(IS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[[N-(diphenylcar bamoy1)-3-phenyl-D-alanyl]amino]imidazole-4--propionamide, whereby the first-named epimer predominates, melting point 106° (from methylene chloride/ether/hexane); from (S)-a-amino-N-f(IS.2S,4S)-l-(eyelohexy1-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and isobutoxycarbonyl-L-phenyl-alanine the isobutyl [(S)-a-[[(S)-l- 226395 - 59 - -[[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexeny1]carbamoy1]-2-imidazo1-4--ylethyl]carbamoyl]phenethyl] carbamate as white crystals, melting point 147° (from ether/ methylene chloride/hexane); from N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionaraide and D-pyro-glutamic acid the (S)-N-[(IS.2S.4S)-l-[cyclo-hexylmethyl]-2-hydroxy-4-isopropyl-5-hexenyl]-a--[(S)-a-[[5-oxo-D-prolyl]amino]hydrocinnanamido]-imidazole-4-propionamide as a white solid. melting point 200° (dec.; from methanol/ethyl acetate/hexane); from N-[(lS.2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropy1-5-hexeny1]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and L-pyro-glutamic acid the (S)-N-[(IS.2S.4S)-l-[cyclo-hexylmethyl]-2-hydroxy-4-isopropyl-5-hexenyl]-a--[(S)-a-[[5-oxo-L-prolyl]amino]hydrocinnamamido]-imidazole-4-propionamide as white crystals, melting point 148° (from methylene chloride/ methanol/ether); from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and N-t-butoxy-carbonyl-a-methyl-L-alanine the t-butyl [l-[C(S)-a-[[(S)-l-[[(IS.2S.4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexenyl]car bamoyl]--2-imidazole-4-ylethyl]carbamoyl]phenethyl]-carbamoyl]-l-methylethyl] carbamate as white crystals, melting point 112° (from methylene chloride/tetrahydrofuran/hexane); from N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L- 22 6 3 9 5 - 60 - -alanyl)imidazole-4-propionamide and Fmoc-Ser(t-Bu)OH the 9H-fluoren-9-yl [(S)-2-t--butoxy-l-[[(S)-a-[[(S)-l-[[(IS.2S.4S)-l-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-phenethyl]carbamoyl]ethyl] carbamate as a white solid, melting point 180° (dec.; from methylene chloride/ether/hexane); from N-[(IS,2S,4S)-l-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and dibenzyl-suberaneacetic acid the (S)-N-[(1S.2S.4S)] -l--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-[[N-(9H-fluoren-9-ylacetyl)-3-phenyl--L-alanyl]amino]imidazole-4-propionamide as white crystals, melting point 119° (from methylene chloride/ether/hexane); from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and adamantyl-acetic acid the (S)-a-[[N-(l-adamantylacetyl)--3-phenyl-L-alanyl]araino]-N-[(IS.2S.4S)-l-[cyclohexylmethyl ) -2-hydr oxy-4- isopr opyl- 5-hexenyl ]-imidazole-4-propionamide as white crystals. melting point 120° (from methylene chloride/ ether/hexane); from (S)-a-amino-N-[(IS.2S.4S)-1-(eyelohexy1-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and phenyloxycarbonyl-L-phenyl-alanine the benzyl [(S)-a-[[(S)-l-[[(IS.2S,4S)--1-(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl] carbamate as white crystals, melting point 144° (from methylene chloride/ ether); 22 6 39 5 - 61 - from (S)-a-amino-N-[(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and 2.2.2-trichloroethoxy-carbonyl-L-phenylalanine the 2.2.2-trichloro-ethyl [(S)-a-[[(S)-l-[[(IS,2S.4S)-1-(cyclohexylmethyl ) -2-hydr oxy-4- isopropyl- 5-hexenyl ]-carbamoyl]-2-imidazol-4-ylethylJcarbamoyl]-phenethyl] carbamate as white crystals, melting point 109° (from methylene chloride/hexane); from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropylhexyl]-a-[(3-phenyl-N-D--prolyl-L-alanyl)amino]imidazole-4-propionamide and 4-imidazolylpropionic acid, which in turn was prepared by hydrogenating urocanic acid, the N-[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[(S)-a-[(R)-l-(3-imidazol-4--y1propionyl]-2-pyrrolidinecarboxamido]hydrocinnamamido] imidazole-4-propionamide in the form of a foam. MS: 760 (M+H)+; from N-[(lS.2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-pheny1-L--alanyl)imidazole-4-propionamide and (R)-l-[(3--hydroxy-2-pyridyl)carbonyl]-2-pyrrolidine-carboxylic acid the (S)-N-[(lS.2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-a--[(S)-a-[(R)-1-[(3-hydroxy-2-pyridyl)carbonyl]-2--pyrrolidinecarboxamido]hydrocinnamamido]imidazole--4-propionamide as a white solid, melting point 198° (dec.; from methylene chloride/methanol/ ether/hexane); from N-[(lS.2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and (R)-l--[(dibenzylacetyl)-2-pyrrolidinecarboxylic acid the (S)-N-[(lS,2S.4S)-l-(cyclohexylmethyl)-2- 22 10 15 - 62 - -hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-[(R)--l-(dibenzylacetyl)-2-pyrrolidinecarboxamido]hydrocinnamamido] imidazole-4-propionamide as white crystals, melting point 104° (from methylene chloride/ether/hexane); - from N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 1-t-butoxy-carbonylaminocyclohexanecarboxylic acid the t-butyl l-[[(S)-a-[[(S)-l-r(lS.2S.4S)-l-(cyclo-hexylmethyl-2-hydroxy-4-isopropyl-5-hexeny1]-2--imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-cyclohexane carbamate as a white solid, MS: 764 (M+H)+; - from N-[(lS,2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropylhexyl]-a-[(3-phenyl-N-D--prolyl-L-alanyl)amino]imidazole-4-propionamide and isovaleric acid the (S)-N-[(1S.2S.4S)-1- -(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]--a-[(S)-a-[(R)-l-isovaleryl-2-pyrrolidine-carboxamido]hydrocinnamamido]imidazole-4-propionamide as a foam. MS: 721 (M+H)+; 25 - from (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2- -hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(D--prolylamino)hydrocinnamamido]imidazole-4-propionamide dihydrochloride and isovaleric acid the (S)-N-[(IS.2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[[(S)-a-[(1-isovaleryl--L-propyl)carbonyl]-3-phenyl-L-alanyl]amino]-imidazole-4-propionamide as a foam, MS: 719 (M+H)+. 20 30 35 The N-[(IS.2S.4S)-l-(eyelohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[(3-pheny1-N-D-prolyl-L-alanyl)amino]-imidazole-4-propionamide used as the starting material was 22 6 3 9 5 - 63 - 10 prepared from the t-butyl (R)-2-[[(S)-a-[[(S)-l--[(IS.2S.4S)-1-(eyelohexylmethyl) -2-hydroxy-4-isopropyl-hexyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]--1-pyrrolidinecarboxylate described in Example 16 by cleaving off the t-butoxycarbonyl group with hydrogen chloride in dioxan in an analogous manner to that described in Example 8. The acids used as starting materials are either known or were prepared as follows: Diphenvlcarbamoy1-L-phenylalanine Treatment of L-phenylalanine with diphenylcarbamoyl chloride in dimethylformamide in the presence of triethyl-amine yields, after recrystallization from methanol/ methylene chloride/hexane, the desired acid in the form of white crystals, melting point 167°. 20 Isobutoxycarbonyl-L-phenylalanine Treatment of L-phenylalanine with isobutyl chloroformate in an analogous manner to that described above yields the desired acid as an oil [MS: 266 (M+H)+] which 25 crystallizes out upon leaving to stand and which is used directly in the next step. Phenyloxvcarbonv1-L-phenylalanine In an analogous manner to that described above, by 30 reacting L-phenylalanine and phenyl chloroformate there is obtained the desired acid in the form of a foam [MS: 286 (M+H)+] which is used directly in the next step. 2.2.2-Trichloroethoxvcarbonyl-L-phenylalanine 35 L-Phenylalanine is reacted with 2,2,2-trichloroethyl chloroformate in a 2N sodium bicarbonate solution, whereby after the usual working-up there is obtained the desired acid as crystals, melting point 126° (from methylene chloride/hexane). 22 6 3 9 5 - 64 - (R)-l-T(3-Hydroxy-2-pyridyl)carbonyl1-2-pyrrolidine-carboxvlic acid 3-Hydroxypicolinic acid is condensed with D-proline benzyl ester in the usual manner and the ester obtained is thereafter converted hydrogenolytically into the desired acid which is used directly in the next step. (R)-1-(Pibenzylacetyl)-2-pyrrolidinecarboxylic acid Dibenzylacetic acid is condensed with D-proline benzyl ester in the usual manner and the ester obtained is converted hydrogenolytically into the desired acid which is used directly in the next step. 1-t-Butoxycarbonylaminocyclohexanecarboxylie acid 1-Aminocyclohexanecarboxylic acid is converted with di-t-butyl dicarbonate in the usual manner into the corresponding N-protected acid which is used directly in the next step. Example 14 40 mg of 9H-fluoren-9-yl [(S)-2-t-butoxy-l-[[(S)-a--[[(S)-1-[[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]ethyl] carbamate are dissolved in 5 ml of methylene chloride and 0.4 ml of piperidine and left to stand at room temperature for 2 hours. Thereafter, the reaction mixture is evaporated to dryness and the residue is chromatographed on silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia. Recrystallization of the thus-obtained crude product yields (S)-a-[[N-(3-t-butoxy-L-alanyl)-3-phenyl--L-alanyl]amino]-N-[(IS,4S)-1-(cyclohexylmethyl)-2-hydroxy--4-isopropyl-5-hexenyl]imidazole-propionamide as a white solid, melting point 103° (dec.; from methylene chloride/ ether/hexane). 22 6 395 10 15 20 25 30 35 - 65 -Example 15 t-Butyl [4[[(S)-a-[[(S)-l-[[(IS.2S.4S)-1-(cyclohexylmethyl )-2-hydroxy-4- isopr opyl- 5-hexeny 1 ] car bamoy 1 ] -2--imidazo1-4-ylethyl]carbamoyl]phenethyl]carbamoyl]butyl] carbamate is dissolved in 0.3N methanolic hydrochloric acid and left to stand at room temperature for 18 hours. Thereafter, the reaction mixture is evaporated to dryness and the residue is chromatographed on silica gel. whereby (S)-a-(5-aminovaleramido)-N-[(S)-1-[[(1S.2S.4S) -1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]hydrocinnamamide dihydro-chloride is obtained as a foam. MS: 637 (M+H)+. In an analogous manner to that described above, but using 3.5N hydrogen chloride in acetic acid, from t-butyl (R)—2—[[(S)-a-[[(S)-l-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropylhexyl]-2-imidazo1-4-ylethyl]carbamoyl] ■ phenethyl]carbamoyl]-l-pyrrolidinecarboxylate, the preparation of which is described in Example 16, there is obtained N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[(3-phenyl-N-D-prolyl-L-alanyl)amino]-imidazole-4-propionamide as a thin-layer chromato-graphically uniform, hygroscopic solid, MS: 635 (M+H)+. Example 16 The following compounds were manufactured by hydrogenating the corresponding olefins in an analogous manner to that described in Example 2: - from ethyl 3-[[(S)-a-[[(S)-l-[[(IS,2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]acrylate the ethyl 22 6 3 9 5 - 66 - [[(S)-a-[[(S)-l-[[(1S.2S.4S)-1-(eyelohexy1-methyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2--imidazo1-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-propionate as a thin-layer chromatographically uniform solid, MS: 668 (M+H)+; from (S)-a-[[N-(l-adamantylacetyl)-3-phenyl-L--alanyl]amino]-N-[(IS.2S,4S)-1-[cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4--propionamide the (S)-a-[(S)-a-[2-(l--adamantyl)acetamido]hydrocinnamamido]-N--[(IS.2S.4S)-l-cyclohexylmethyl)-2-hydroxy-4--isopropylhexyl]imidazole-4-propionamide as a white solid. MS: 717 (M+H)+; from (S)-N-[(IS.2S,4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(3--pyridineacetamido)hydrocinnamamido]imidazole-4--propionamide the (S)-N-[(IS.2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropylhexyl]-a-[(S)--a-[2-(3-pyr idyl)acetamido]hydrocinnamamido]-imidazole-4-propionamide as white crystals. melting point 211° (from methylene chloride/ methanol/ether); from (S)-N-[(lS.2S.4S)-l-[cyclohexylmethyl]-2--hydroxy-4-isopropyl-5-hexenyl]-a[(S)-a-[[5--oxo-L-prolyl]amino]hydrocinnamamido]imidazole-4--propionamide the (S)-N-[(lS,2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropylhexyl]-a-[(S)--a-[(S)-5-oxo-2-pyrrolidinecarboxamido]hydro-cinnamamido]imidazole-4-propionamide as a thin--layer chromatographically uniform solid, MS: 651 (M+H)+; from the epimer mixture of (S)-N-[(1S.2S,4S)-1--[eyelohexylmethyl]-2-hydroxy-4-isopropyl-5--hexenyl]-a-[(S)-a-[[5-oxo-D-prolyl]amino]-hydrocinnamamido]imidazole-4-propionamide and 22 6 3 9 5 10 - 67 - (S)-N-[(1S.2S.4S)]-l-[eyelohexylmethyl]-2-hydroxy--4-isopropyl-5-hexenyl]-a-[(S)-a-[[5-oxo-L--prolyl]amino]hydrocinnamamido]imidazole-4-propion-amide the (S)-N-[(lS,2S,4S)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropylhexyl]-a-[(S)-a-[(RS)-5--oxo-2-pyrrolidinecarboxamido]hydrocinnamamido]-imidazole-4-propionamide as a solid, MS: 651 (M+H)+: - from (S)-N-f(lS,2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[[N-(9H--fluoren-9-ylacetyl)-3-phenyl-L-alanyl]amino]-imidazole-4-propionamide the (S)-N-[(1S,2S,4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropylhexyl]--a-[(S)-a-[2-(10,ll-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)acetamido]hydrocinnamamido]-imidazole-4-propionamide as a thin-layer chromatographically uniform white solid, MS: 775 20 25 30 35 (M+H)+; from (S)-N-[(IS,2S,4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[[N-(diphenyl-carbamoyl)-3-phenyl-D-alanyl]amino]imidazole-4--propionamide the ethyl [(S)-a-[[(S)-l--[[(lS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropylhexyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl] carbamate as white crystals, melting point 196° (from methanol/methylene chloride/ether); from benzyl [(S)-a-[[(S)-l-[[(IS,2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl] carbamate the phenyl [ (S)-<x-[[ (S)-l-[ [ (IS, 2S.4S)-1-(cyclohexylmethyl)--2-hydroxy-4-isopropylhexy1]carbamoyl]-2-imidazo1--4-ylethyl]carbamoyl]phenethyl] carbamate as white crystals, melting point 157° (from methylene chloride/methanol/ether); 22 6 3 9 10 15 20 25 30 35 - 68 - from (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(4--nitrocinnamamido)hydrocinnamamido]imidazole-4--propionamide the (S)-a-[(S)-a-(4-aminohydro-cinnamamido)hydrocinnamamido]-N-[(IS.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropylhexyl]-imidazole-4-propionamide as white crystals, melting point 174° (from methylene chloride/ methanol/ether); from (2S.3S.5S)-2-(Boc-D-Pro-Phe-His-NH)-1-cyclo hexyl-5-isopropyl-6-hepten-3-ol the t-butyl (R)-2-[[(S)-a-[[(S)-l-[(IS.2S.4S)-l-(cyclohexylmethyl) -2- hydr oxy-4- isopr opy lhexyl] -2- imidazo 1-4 -ylethyl]carbamoyl]phenethyl]carbamoyl]-l--pyrrolidinecarboxylate as white crystals, melting point 173° (from methylene chloride/ methanol/hexane); from (S)-N-t(IS.2S.4S)-l-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(4--oxavaleramido)hydrocinnamamido]imidazole-4--propionamide the (S)-N-[(IS.2S.4S)-1-(cyclohexylmethyl ) -2-hydr oxy- 4- isopr opy lhexyl] -a- [ (S)--a-(4-oxovaleramido)hydrocinnamamido]imidazole-4 -propionamide as a foam. MS: 638 (M+H)+; from (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(4--hydroxyhydrocinnamamido)hydrocinnamamido]-imidazole-4-propionamide the (S)-N-[(IS.2S.4S)-1 -(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]--a-[(S)-a-(4-hydroxyhydroc innamamido)hydro-cinnamamido]imidazole-4-propionamide as a white solid, melting point 120° (dec.; from methylene chloride/ether/hexane); from (S)-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(3- 22 6 3 9 5 - 69 - -pyridineacrylamido)hydrocinnamamido]imidazole-4--propionamide the (S)-N-[(lS.2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropylhexyl]-a-[(S)— -a-[3-(3-pyridyl)propionamido]hydrocinnamamido]-imidazole-4-propionamide as white crystals, melting point 195° (from methanol/ether/hexane); from (S)-N-[(IS.2S.4S)-1-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl[-a-[(S)-a--nicotinamidohydrocinnamamido]imidazole-4-propionamide the N-[(S)-a-[[(S)-l-[[(1S,2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-phenethyl]nicotinamide as a white solid, melting point 112° (dec.; from methylene chloride/ether/ hexane); from (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a--(imidazo1-4-acrylamido)hydrocinnamamido]imidazole--4-propionamide the N-[(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl]-a-[(S)-a--imidazole-4-propionamidohydrocinnamamido]-imidazole-4-propionamide as white crystals. melting point 118° (from methanol/ether/hexane); from t-butyl [1-[[(S)-a-[[(S)-l-[[(IS,2S,4S)-l--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]-l-methylethyl] carbamate the t-butyl [l-[[(S)-a-[[(S)-l--[[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropylhexyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]hydrocinnamoyl]carbamoyl]-1-methylethyl] carbamate as a foam, MS: 725 (M+H)*. 22 6 3 9 5 - 70 -Example 17 A mixture of 95 mg (0.133 mmol) of N-[(IS,2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]-a-[(3--phenyl-N-D-prolyl-L-alanyl)amino]imidazole-4-propionamide, 0.025 ml (0.199 mmol) of pivaloyl chloride and 0.185 ml Q (1.33 mmol) of triethylamine in 10 ml of tetrahydrofuran is stirred at room temperature overnight. After usual working-up and chromatographic purification on silica gel with a 20:1:0.1 mixture of methylene chloride, methanol and ammonia there is obtained (S)-N-f(lS.2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy -4-isopropylhexyl]-a-[(S)-a--[(R)-l-pivaloyl-2-piperidinecarboxamido]hydrocinnamamido]-imidazole-4-propionamide as a thin-layer chromatographically uniform solid. MS: 722 (M+H)+. Example 18 20 20 mg of (S)-a-[[N-(3-t-butoxy-L-alanyl)-3-phenyl-L--alanyl]amino]-N-[(IS.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-propionamide are dissolved in 1 ml of aqueous trifluoroacetic acid (95%) and stirred 25 at room temperature for 2.5 hours. Evaporation of the reaction mixture and chromatographic purification on silica gel with a 8:1:0.1 mixture of methylene chloride, methanol and ammonia yields thin-layer chromatographically uniform (S)-N-[(IS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy- 30 -4-isopropyl-5-hexenyl]-a-[[N-(L-serylamino)-3-phenyl-L--alanyl]amino]imidazole-4-propionamide. MS: 625 (M+H)+. Example 19 35 195 mg of N-[(R)-2-benzyl-5,5-dimethyl-4-oxohexanoyl]--N-methyl-L-histidine benzyl ester are hydrogenated in the presence of 25 mg of palladium-on-carbon (5%) for 2 hours 22 6 3 9 5 10 15 - 71 - and the N-[(R)-2-benzyl-5.5-dimethyl-4-oxohexanoyl]-N--methyl-L-histidine obtained is reacted in the usual manner with (aS.BS)-fl-amino-a-[(S)-2-isopropyl-3--butenyl]cyclohexanepropanol. Chromatographic purification of the crude product obtained on silica gel with a 140:10:0.1 mixture of methylene chloride, methanol and ammonia yields N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl -5-hexenyl]-a-[(R)-2-benzyl-N.5.5--trimethyl -4-oxohexanamido]imidazole-4-propionamide as a thin-layer chromatographically uniform substance. MS: 635 (M+H)+. The less polar epimeric N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexeny1]-a-[(R)-2-benzyl--N.5.5-trimethy1-4-oxohexanamido]imidazole-4-propionamide. MS: 635 (M+H)+. is obtained as a byproduct. The N-[(R)-2-benzyl-5.5-dimethyl-4-oxohexanoyl]-N--methyl-L-histidine benzyl ester used as the starting material was prepared by condensing N-(a-methyl)-L--histidine benzyl ester with 2-(R)-benzyl-4-oxo-5,5.5--trimethylvaleric acid and was used directly in the next step. Example 20 100 mg (0.164 mmol) of ethyl (R)-3-[[(S)-l--[[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-4--phenylbutyrate are stirred at room temperature for 3 hours in a solution of 30% hydrazine hydrate in methanol. Thereafter, the reaction mixture is evaporated 35 and the residue is chromatographed on silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia. Crystallization of the thus-obtained crude product from methanol/methylene chloride/ether yields 20 25 30 10 15 20 25 30 35 22 6 3 9 5 - 72 - (R)-3-[[(S)-l-[[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoy1]-2-imidazo1-4-ylethyl]-carbamoyl]4-phenylbutyrohydrazide as white crystals. melting point 109°. The ethyl (R)-3-[[(S)-l-[[(IS.2S.4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate used as the starting material was prepared as described in Example 40. Example 21 0.083 ml (0.54 mmol) of 4-piperidinecarboxylic acid ethyl ester is reacted at room temperature with 210 mg (0.36 mmol) of ethyl 1-[(R)-3-[[(S)-l-[[(IS.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoy1]-2-imidazol-4-yl-ylethyl]carbamoy1]-4-phenyl-butyryl]carboxylate in 20 ml of acetonitrile in the presence of bis-(2-oxo-3-oxazolidinyl)phosphine chloride. After working-up in the usual manner and chromatography on silica gel there is obtained ethyl 1-[(R)-3-[[(S)-l--[[(lS.2S.4S)-l-(cyclohexylmethyl) -2-hydroxy-4-isopropyl--5-hexenyl]carbamoyl]-2-imidazol -4-ylethyl]carbamoyl]-4--phenylbutyryl]-4-piperidinecarboxylate as a foam. MS: 720 (M+H)+. The following compounds were manufactured in an analogous manner to that described above: - from (R)-3-[[(S)-l-[[(lS.2S.4S)-l-(eyelohexy1-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl] -2-imidazo1-4-ylethy1]carbamoy1]-4-phenylbutyric acid and L-prolinol the (S)-N-[(IS.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5- 22 6 39 5 - 73 - 10 15 20 25 30 35 -hexenyl]-a-[(R)-a-[[(2-hydroxymethyl)-l--pyrrolidinyl]carbony1]methyl]hydrocinnamamido]-imidazole-4-propionamide as a white solid, melting point 103° (dec.; from methylene chloride/ether/hexane); - from (R)-3-[[(S)-l-[[(lS,2S,4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexeny1]carbamoyl] -2-imidazo1-4-ylethyl]carbamoy1]-4-phenylbutyr ic acid and N-methylethanolamine the (S)-N- -[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(R)-a-[[(2-hydroxy-ethyl)methylcarbamoyl]methyl]hydrocinnamamido]-imidazole-4-propionamide as a white solid, melting point 82° (dec.; from methylene chloride/ ether/hexane); - from (R)-3-[[(S)-l-[[(lS.2S,4S)-l-(cyclohexyl- methyl)-2-hydroxy-4-isopropyl-5-hexeny1]carbamoyl] -2-imidazo1-4-ylethy1]carbamoyl]-4-phenylbutyric acid and N.N-dimethylethylenediamine the (S)-N--[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(R)-a-[[[2-(dimethy1-amino)ethyl]carbamoyl]methyl]hydrocinnamamido]-imidazole-4-propionamide as a white solid, melting point 98° (from methylene chloride/ hexane); - from (R)-3-[[(S)-l-[[(lS.2S.4S)-l-(eyelohexy1- methy1)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl] -2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyric acid and N.N-dimethylpropylenediamine the (S)-N--[(1S.2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(R)-a-[[[3-(dimethyl-amino)propyl]carbamoyl]methyl]hydrocinnamamido]-imidazole-4-propionamide as white crystals. melting point 98° (from methylene chloride/ether). 22 6 3 9 5 10 15 20 25 30 35 - 74 - The (R)-3-[[(S)-l-[[(IS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]-4-phenylbutyric acid used as the starting material was prepared as follows: 100 mg (0.16 mmol) of ethyl (R)-3-[[(S)-l--[[(lS.2S.4S)-l-cyclohexylmethyl)-2 -hydroxy-4-isopropyl--5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-4--phenylbutyrate (see Example 40) in 3 ml of ethanol are treated with 0.66 ml of 0.5N (0.33 mmol) sodium hydroxide solution and stirred at room temperature for 2.5 hours. The mixture is then neutralized with 0.33 ml (0.33 mmol) of IN hydrochloric acid, ethyl acetate is added thereto and the mixture is washed with saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and the solvent is removed under reduced pressure, whereby there are obtained 91 mg (95%) of (R)-3--[[(S)-l-[[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexeny1]carbamoy1]-2-imidazo1-4 -ylethyl]-carbamoyl]-4-phenylbutyric acid as an amorphous powder. MS: 581 (M+H)+. Example 22 70 mg (0.1 mmol) of ethyl l-[(R)-3-[[(S)-l--[[(IS.2S.4S)-1-(cyclohexylmethyl) -2-hydroxy-4-isopropyl--5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-4--phenylbutyryl]-4-piperidinecarboxylate are suspended in IN sodium hydroxide solution in a 9:1 mixture of methanol and water and stirred at room temperature for 3 hours. Thereafter, the solvent is evaporated and the residue is recrystallized from methanol/methylene chloride/hexane. whereby 1-[(R)-3-[[(S)-l-[[(IS.2S.4S)-1-(cyclohexylmethyl ) -2 -hydr oxy-4- isopr opyl-5-hexenyl ] car bamoyl ] -2--imidazo1-4-ylethy1]carbamoyl]-4-phenylbutyryl]-4- 22 6 3 9 5 10 15 20 25 30 35 - 75 - -piperidinecarboxylic acid is obtained as white crystals, melting point 169°. Example 23 Reaction of (S)-N-[(IS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[(S)-a-(D-prolyl-amino)hydrocinnamamido]imidazole-4-propionaraide dihydro-chloride (see Example 8) with Fmoc-Ser(t-Bu)OH in an analogous manner to that described in Example 1. treatment of the Fmoc-protected compound obtained with piperidine and subsequent chromatography of the crude product on silica gel with a 200:10:1 mixture of methylene chloride, methanol and anunonia yields thin-layer chromatographically pure (S)-a-[[N-[1-(3-butoxy-L-alanyl)-D-propyl]-3--phenyl-D-alanyl]amino]-N-[(2S.3S,4S)-3-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide as a foam. MS: 779 (M+H)+. Example 24 A mixture of 100 mg (0.17 mmol) of 2-t-butyl [(S)-a--[[(S)-l-[[(IS.2S.4S)-2-hydroxy-1-isobuty1-4-isopropyl-5--hexeny1]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-phenethyl] carbamate and 65 mg (0.25 mmol) of osmium tetroxide in 20 ml of pyridine is stirred at room temperature overnight. Thereafter. 4 ml of 33% sodium bisulphite solution are added and the mixture is stirred for a further hour. Chromatography of the crude product, obtained after the usual working-up, on 20 g of silica gel with a 9:1:0.1 mixture of chloroform, methanol and ammonia yields 65 mg of thin-layer chromatographically uniform (2RS.3S.5S.6S)-6-(Boc-Phe-His-NH)-3-isopropyl-8-methyl--1.2.5-nonanetriol. MS: 632 (M+H)+. 22 6 3 9 5 4 - 76 - 10 15 20 Example 25 A mixture of 411 mg (0.82 mmol) of (RS)-a-[[(S)-a--(Boc-Pro-NH)phenethy1]carbamoy1]imidazole-4-propionic acid. 200 mg (0.82 mmol) of (aS.BS)-fl-amino-a-[(S)-2--isopropyl-3 -butenyl]cyclohexanepropanol. 0.1 ml (0.82 mmol) of 4-ethylmorpholine. 222 mg (1.64 mmol) of HOBT and 203 mg (0.99 mmol) of DCC is dissolved in 20 ml of dimethylformamide and stirred at room temperature for 2 days. The separated precipitate is filtered off and the solvent is evaporated under reduced pressure. After usual working-up there are obtained 590 mg of a crude product which is chromatographed on 30 g of silica gel with a 20:1:0.1 mixture of methylene chloride, methanol and ammonia. Recrystallization of the thin-layer chromatographically uniform product from methylene chloride/ether/ hexane yields 260 mg of t-butyl (S)-2-[[(S)-a-[(RS)--a-[[(IS.2S,4S)-1 -(cyclohexylmethyl-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]imidazole-3-propionamido]-phenethyl]carbamoyl]-l-pyrrolidinecarboxylate as crystals, melting point 112°. The (RS)-a-[[(S)-a-(Boc-Pro-NH)phenethyl]-carbamoyl]imidazole-4-propionic acid used as the starting material was prepared as follows: 10.8 g (30 mmol) of Boc-Pro-Phe-OH and 3.0 g (30 mmol) of N-methylmorpholine are dissolved in 120 ml of tetrahydrofuran and cooled to -20°. 4.1 g of isobutyl chloro-formate in 15 ml of tetrahydrofuran are added dropwise to this solution and after 5 minutes at -20° a solution of 3.9 g (60 mmol) of sodium azide in 30 ml of water is added 35 dropwise. After completion of the addition the mixture is stirred at 0° for 30 minutes, then diluted with ice-cold ethyl acetate to double the volume and the reaction 25 30 226395 10 15 - 77 - mixture is subsequently treated firstly with cold saturated sodium bicarbonate solution and then with cold saturated sodium chloride solution. The organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure at a temperature of 20-25°. The residue is dissolved in 300 ml of toluene under a nitrogen atmosphere and heated to 80°. 4.9 g (45 mmol. 1.5 mol equivalents) of benzyl alcohol are then added and the reaction mixture is heated to reflux for 6 hours. After cooling and evaporating the reaction solution the residue is triturated with a 1:1 mixture of ether and hexane and the separated precipitate is filtered off. After drying the filtrate under reduced pressure there are obtained 11 g (79%) of [(R)-l-(Boc-Pro-NH)-l-(benzylamino)ethyl]-benzene, melting point 155-157°. 4.7 g (10 mmol) of the above compound in 300 ml of tetrahydrofuran are hydrogenated for 3 hours in the presence of 1.0 g of palladium-on-carbon at 343.25 kPa. After completion of the hydrogen uptake the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is dissolved in 60 ml of dimethyl-25 formamide and 1.98 g (10 mmol) of (RS)-(imidazol-4- 4 -ylmethyl)malonic acid monomethyl ester . The solution obtained is then cooled to 0° and treated with 3.0 g (20 mmol) of HOBT and 2.2 g (12 mmol) of EDC. The reaction mixture is then left to warm to room temperature and is 30 stirred at this temperature for 48 hours. After evaporating the reaction mixture in a high vacuum the residue is dissolved in ethyl acetate, washed with water and subsequently extracted with IN citric acid. The citric acid extract is neutralized with sodium bicarbonate and 35 extracted with ethyl acetate. The organic extract is then dried over sodium sulphate and evaporated under reduced pressure. Chromatography of the residue on silica gel and 20 4 M. Goodman et al.. Int. J. Pept. Prot. Res. 12. 72-88 (1981) 226J95 - 78 - recrystallization of the crude product obtained from ethyl acetate/ether yields 2.5 g (49%) of (RS)-a-[[(S)-a- 5 -(Boc-Pro-NH)-phenethyl]carbamoyl]imidazole-4-propionic acid methyl ester, melting point 142-143°. 1.54 g (3 mmol) of the above ester are dissolved in 6 ml of ethanol and treated with 3.15 ml (3.15 mmol. 1.05 mol equivalents) of IN sodium hydroxide solution. After stirring for 3 hours while cooling with ice 3.15 ml (3.15 mmol) of IN H2SC>4 are added and the reaction mixture is evaporated under reduced pressure. The residue is triturated with 300 ml of ethanol and the insoluble sodium sulphate is filtered off. Concentration of the ethanolic solution yields 1.47 g (98%) of (RS)-a-[[(S)--a-(Boc-Pro-NH)phenethyl]carbamoyl]imidazole-4-propionic acid, melting point 120° (dec.). 20 Example 26 g A mixture of 1.05 g (2.06 mmol) of Boc-Phe-His(Bom)-OH, 0.5 g (2.06 mmol) of (aS.BS)-fl-amino-a-[(S)-2--isopropyl-3-butenyl]cyclohexanepropanol, 0.26 ml 25 (2.06 mmol) of 4-ethylmorpholine. 0.56 g (4.12 mmol) of HOBT and 0.51 g (2.47 mmol) of DCC in 40 ml of dimethyl-formamide is stirred at room temperature overnight. Separated urea is then filtered off and the solvent in evaporated under reduced pressure. Working-up of the 30 residue in the usual manner yields 1.69 g of t-butyl [(S)-l-benzyl-2-[[(S)-1-[[(1S.2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]carbamoy1]-2-imidazo1-4--ylethyl]amino]ethyl] carbamate which is used directly in the next step. 35 1.69 g (about 2.06 mmol) of t-butyl [(S)-l-benzyl-2--[C(S)-l-[[(lS,2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4- 22 6 39 5 10 15 20 25 30 35 - 79 - -isopropy1-4-hexeny1]carbamoyl]-2-imidazo1-4-ylethy1]amino] ethyl] carbamate are hydrogenated at room temperature overnight in the presence of 0.5 g of palladium-on-carbon (5%) in 50 ml of a 4:1 mixture of acetic acid and water and 0.8 g of N.N'-dimethylethylenediamine. After completion of the hydrogen uptake the catalyst is filtered off and the filtrate is evaporated and treated twice in succession firstly with toluene and then again evaporated to dryness. Chromatography of the residue on 180 g of silica gel with a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent yields 1.13 g of a crude product which is recrystallized from methylene chloride/ether/hexane. whereby there are obtained 730 mg of t-butyl [(S)-l-benzyl-2-[[(S)-l-[[(is.2S.4S)-l-(cyclohexylmethyl ) -2-hydr oxy-4- isopr opy lhexyl] car bamoyl] -2--imidazol-4-ylethyl]amino]ethyl] carbamate as crystals. melting point 144°. £ The Boc-Phe-His(Bom)OH. used as the starting material was prepared as follows: 58 g of Boc-Phe-His(Bom)OMe. which was prepared by coupling Boc-Phe-OH with His(Bom)OMe according to usual methods. 30.35 g of Lawesson reagent and 700 ml of benzene are heated to reflux overnight. Thereafter, the reaction mixture is cooled and evaporated to dryness. The residue is then filtered through 1.5 g of silica gel firstly with methylene chloride and then with methylene chloride with the progressive addition of ethanol (up to 7%). There are thus obtained 35.56 g of [(S)-2-(Boc-NH)-3-phenylthio-propionyl]His(Bom)OMe in the form of a foam. MS: 553 (M+H)+. 0.5 g of the above thio compound and 5 g of Raney--nickel in 30 ml of ethanol are stirred in a hydrogen 22 6 3 9 5 ' 10 15 - 80 - atmosphere for 2 hours. The catalyst is then filtered off and the filtrate is evaporated. Chromatography of the crude product on 30 g of silica gel with chloroform, a 98:2 mixture of chloroform and ethanol and a 95:5 mixture of chloroform and ethanol as the eluting agent yields 0.24 g of [(S)-2-(Boc-NH)-3-phenylpropyl]His(Bom)OMe in the form of a foam, MS; 523 (M+H)+. 170 mg of the above ester in 2 ml of IN sodium hydroxide solution in a 1:1 mixture of methanol and water are stirred at room temperature overnight. 1 ml of conc. acetic acid is then added and the reaction mixture is evaporated under reduced pressure. The residue is warmed three times with 150 ml of methanol each time and decanted off. The methanolic phase is evaporated and the residue is chromatographed on 30 g of silica gel with a 4:1:1 mixture of butanol. acetic acid and water, whereby there are obtained 100 mg of [(S)-2-(Boc-NH)-3-phenylpropyl]~ His(Bom)OH in form of a foam. MS: 509 (M+H)+. Example 27 25 0.17 g (0.56 mmol) of 2-(RS)-benzyl-4-(4-chloro- phenyl)-4-oxo-butyric acid is dissolved in 10 ml of dimethylformamide and treated with 0.20 g (0.51 mmol) of (S)-a-amino-N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide. 0.057 g (0.56 mmol) of triethylamine and 0.21 g (0.56 mmol) of HBTU and stirred at room temperature overnight. The mixture is subsequently evaporated in a high vacuum. The residue is dissolved in ethyl acetate and then washed with saturated sodium bicarbonate solution and 35 saturated sodium chloride solution. After drying the organic phase over sodium sulphate the solvent is evaporated under reduced pressure and the residue, for 20 30 22 6 39 15 - 81 - purification, is chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol which ^ contains 0.5% ammonium hydroxide. In this manner there are obtained 270 mg (78%) of (S)-a-[(RS)-a-(4-chloro-phenylacety1)hydrocinnamamido] -N-[(IS,2S.4S)-1-(eyelohexy lme thyl) -2-hydr oxy-4- isopr opyl- 5-hexenyl] imidazo le-4 - -propionamide in the form of a yellowish foam. lO + MS: 675 (M ). The 2-(RS)-benzy1-4-(4-chlorophenyl)-4-oxo-butyric acid used as the starting material was prepared as follows 5.0 g (20 mmol) of benzylmalonic acid diethyl ester are added dropwise at room temperature to a suspension of 0.87 g of sodium hydride dispersion (55% in oil) in 20 ml of dimethylformamide. Subsequently, the reaction mixture is stirred at room temperature for 20 minutes and thereafter 4.67 g (20 mmol) of omega-bromo-4-chloroaceta-phenone in 25 ml of dimethylformamide are added dropwise. After completion of the addition the deep brown coloured reaction mixture is stirred at room temperature overnight and thereafter evaporated in a high vacuum. The residue is dissolved in methylene chloride, washed with water and 25 dried over sodium sulphate. Thereafter, the solvent is evaporated under reduced pressure and the residue, for purification, is chromatographed on silica gel with a 6:1 mixture of hexane and ether, whereby there are obtained 5.17 g (64%) of 2-(RS)-benzyl-2-carbethoxy-4-(4-chlorophenyl )-4-oxobutyric acid as a yellowish solid. MS: 357 (M-OC2H5)+. 311 (M-benzyl)+. 20 30 6.15 ml (3 mol equivalents) of 2N sodium hydroxide solution are added to a solution of 1.64 g (4.1 mmol) of 35 the above-named ethyl ester in 10 ml of ethanol and 9 ml of water and the reaction mixture is stirred at room temperature for 16 hours. The mixture is subsequently 22 6 3 9 5 10 15 - 82 - adjusted to pH 3 with IN hydrochloric acid and extracted with methylene chloride. The organic phase is dried over sodium sulphate, evaporated under reduced pressure and the crystalline residue is heated to 150-160° until the C02 evolution has terminated. After cooling the residue is dissolved in ether and brought to crystallization by the addition of hexane. There are thus obtained 970 mg (79%) of 2-(RS)-benzyl-4-(4-chlorophenyl)-4-oxobutyric acid as yellowish crystals, melting point 137-138°. Example 28 1.57 g (4.03 mmol) of (S)-a-amino-N-[(1S.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-imidazole-4-propionamide. 0.45 g (4.43 mmol) of triethyl-amine and 1.68 g (4.43 mmol) of HBTU are added to a solution of 1.45 g (4.43 mmol) of 2-(RS)-(l-naphthyl- 20 5 methyl)-3-morpholinocarbonylpropionic acid in 60 ml of dimethylformamide. The yellow reaction solution obtained is then stirred at room temperature for 15 hours and subsequently evaporated in a high vacuum. The residue is dissolved in 150 ml of methylene chloride, the organic 2 5 phase is washed twice with 30 ml of saturated sodium bicarbonate solution and 30 ml of water, dried over sodium sulphate and evaporated under reduced pressure. For purification and separation of the two epimers. the residue is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol which contains 0.5% ammonium hydroxide. There are thus obtained 855 mg (30%) of an isomer with the Rf value 0.45 and 726 mg (26%) of an isomer with the Rf value 0.33. Both isomers exhibit the same mass spectrum. MS: 700 (M+H)+. 30 35 The 2-(RS)-(1-naphthylmethyl)-3-morpholinocarbonyl-propionic acid used as the starting material was prepared as follows: 5 EPA 0.200.406 22 6 3 9 5 10 15 20 30 35 - 83 - 1.10 9 (12.6 mmol) of morpholine, 2.42 g (12.6 mmol) of EDC and 3.43 g (25.2 mmol) of HOBT are added to a solution of 3.63 g (12.6 mmol) of 3-ethoxycarbonyl-4-(1--naphthyl)butyric acid6 in 50 ml of dimethylformamide and the reaction solution is stirred at room temperature for 15 hours and subsequently evaporated in a high vacuum. The residue is dissolved in ethyl acetate and the organic phase is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel with a 98:2 mixture of methylene chloride and ethanol, whereby there are obtained 3.78 g (84%) of 2-(RS)-(l--naphthylmethyl)-3-morpholinocarbonylpropionic acid ethyl ester as a yellowish oil which begins to crystallize out after lengthy standing. MS: 355 (M+) 1.7 g (4.78 mmol) of the above-named ethyl ester are dissolved in 6 ml of ethanol and, after the addition of 7.2 ml (7.2 mmol) of IN sodium hydroxide solution, stirred at 50° for 3 hours. After cooling 7.5 ml (7.5 mmol) of IN 25 hydrochloric acid are added to the deep yellow reaction solution and the mixture is subsequently evaporated under reduced pressure. The residue is dissolved in 100 ml of methylene chloride and the organic phase is washed twice with 20 ml of water, dried over sodium sulphate and evaporated under reduced pressure, whereby there are obtained 1.45 g (92%) of 2-(RS)-(l-naphthylmethyl)-3--morpholinocarbonylpropionic acid as a yellow foam which is used directly in the next step. MS: 327 (M+) 6 EPA 0.181.110 22 6 3 9 5 10 - 84 -Example 29 109 mg (0.38 mmol) of 3-(RS)-(1-naphthylmethyl)-succinic acid 1-ethyl ester are dissolved in 6 ml of acetonitrile and 1 ml of dimethylformamide and, after the addition of 135 mg (0.35 mmol) of (S)-a-amino-N--[(IS.2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide. 39 mg (0.38 mmol) of triethylamine and 144 mg (0.38 mmol) of HBTU. stirred at room temperature for 6 hours. Subsequently, the reaction solution is evaporated in a high vacuum and the residue is dissolved in 50 ml of ethyl acetate and washed 3 times ^ with 10 ml of saturated sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated under reduced pressure, and the residue is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol which contains 0.1% ammonium hydroxide, 20 whereby there are obtained 103 mg (45%) of (RS)-fl-[[(S)-l--[[(1S,2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexeny1]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-1--naphthylbutyric acid ethyl ester as a yellowish foam. MS: 594 (M-ethanol-water)+ 25 The 3-(RS)-(1-naphthylmethyl)succinic acid 1-ethyl ester used as the starting material was prepared as foilows: 820 mg (3.44 mmol) of 2-(l-naphthylmethylene)succinic 30 acid anhydride6 are heated to reflux for 4 hours in 5 ml of ethanol. Subsequently, the reaction mixture is evaporated under reduced pressure, the residue is taken up in 10 ml of saturated sodium bicarbonate solution and extracted with ether. The aqueous phase is acidified with 35 in hydrochloric acid and extracted with ether. After drying the ether extract over sodium sulphate and evaporation under reduced pressure there remain 710 mg (73%) of 3-(RS)-(l-naphthylmethylene)succinic acid 1-ethyl ester. 6 EPA 0.181.110 10 15 20 25 30 35 22 6 3 - 85 - These 710 mg (2.5 mmol) of ethyl ester are dissolved in 5 ml of ethanol and hydrogenated for 15 hours in the presence of 100 mg of palladium-on-carbon. Thereafter, the catalyst is filtered off, the filtrate is evaporated under reduced pressure and the residue is chromatographed on silica gel with a 98:2 mixture of methylene chloride and methanol, whereby there are obtained 190 mg (27%) of 3-(RS)-(l-naphthylmethyl)succinic acid 1-ethyl ester. MS: 286 (M)+ Example 30 In an analogous manner to that described in Example 27. by condensing (aRS.S)-a-benzyl-l-t-butoxy-carbonyl-Y-oxo-2-pyrrolidinebutyric acid with (S)-a--amino-N-[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and subsequent epimer separation by chromatography there were obtained t-butyl (S)-2-[[(S)-a-[[(S)-l-[[(1S.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoy1]phenethyl]acetyl] -1-pyrrolidinecarboxylate (less polar isomer) and t-butyl (S)-2-[[(R)-a-[[(S)-l-[[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]phenethyl]acetyl]-l-pyrrolidine-carboxylate. MS: 734 (M+H)+ The (aRS.S)-a-benzyl-l-t-butoxycarbonyl-y-oxo-2--pyrrolidinebutyric acid used as the starting material was 7 obtained from N-t-butoxycarbonyl-prolyl-bromomethane and benzylmalonic acid diethyl ester in analogy to the preparation of 2-(RS)-benzyl-4-(4-chlorophenyl)-4-oxo-butyric acid (see Example 27). MS: 362 (M+H)+. 7 EPA 0.029.163 22 6 3 9 5 10 15 - 86 -Example 31 In an analogous manner to that described in Example 2. by catalytically hydrogenating t-butyl (S)-2-[[(S)-a--[[(S)-l-[[(Is.2S.4S)-l-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl]acetyl]-l-pyrrolidinecarboxylate and t-butyl (S)-2-[[(R)-a-[[(S)-l-[[(1S.2S.4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2--imidazo1-4-ylethyl]carbamoyl]phenethy1]acetyl]-l--pyrrolidinecarboxylate there were obtained t-butyl (S)-2--[[(S)-a-[[(S)-1-[[(1S.2S.4S)-1-(cyclohexylmethyl) -2--hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoy1]phenethyl]acety1]-1-pyrrolidinecarboxylate (less polar isomer) and t-butyl (S)-2-[[(R)-a-[[(S)-l--[[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-hexyl]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]phenethyl]-acetyl]-l-pyrrolidinecarboxylate. MS: 736 (M+H)+ Example 32 25 in an analogous manner to that described in Example 1. l-[l-[(RS)-3-[[(S)-l-[[(IS.2S.4S)-1(eyelohexylmethyl)-2--hydroxy-4-isopropylhexyl]carbamoy1]-2-imidazo1-4-y1--ethy1]carbamoyl]-4-phenybutyryl]-D-prolyl]-L-proline benzyl ester was manufactured as a mixture of 2 epimers by condensing (S)-a-amino-N-[(IS.2S.4S)-l-(cyclohexylmethyl )-2-hydroxy-4-isopropylhexyl]imidazole-4-propionamide with (aRS.2R)-a-benzyl-2-C[(S)—2—[(benzyloxy)-carbonyl ]-l-pyrrolidinyl] carbonyl ]--r-oxo-l-pyr rolidine-butyric acid. 35 MS: 867 (M+H)+ 20 30 10 15 20 25 30 35 22 6 3 - 87 - The acid used as the starting material was prepared as follows: 2-Benzyl-3-methoxycarbonylpropionic acid t-butyl ester. MS: 222 (M-C4Hg)+. was prepared starting from 2-benzyl-3-methoxycarbonylpropionic acid8 according to the procedure described by U. Widmer in Synthesis 1983. page 135. 415 mg of the above t-butyl ester are dissolved in 3 ml of t-butyl alcohol and stirred at room temperature for 3 hours in the presence of 1.5 ml of IN sodium hydroxide solution. The reaction solution is then evaporated under reduced pressure and the residue is dissolved in water and washed with ether. The aqueous phase is thereafter neutralized with 1.5 ml of IN hydrochloric acid and extracted with methylene chloride. The organic extracts are dried over sodium sulphate and evaporated under reduced pressure, whereby there is obtained 2-benzyl-3-carboxypropionic acid t-butyl ester as a colourless oil. MS: 208 (M-C4Hg)+. 370 mg (1.4 mmol) of the above-named half ester. 409 mg (1.2 mmol) of H-D-Pro-Pro-OBz and 270 mg (2 mol equivalents) of triethylamine are dissolved in 8 ml of dimethylformamide. 530 mg (1.4 mmol) of HBTU are added to this solution and the reaction mixture is stirred at room temperature for 15 hours and subsequently evaporated to dryness in a high vacuum. The residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. Chromatography of the residue on silica gel with a 98:2 mixture of methylene chloride and methanol yields (aRS.2R)-a-benzyl-2--[[(S)-2-[(benzyloxy)carbonyl]-l-pyrrolidinyl]carbonyl]-y- 8 L.D. Byers und R. Wolfenden, J. Biol. Chem.. 247. 606 (1972) 22 6 3 9 5 10 15 20 30 - 88 - -oxo-l-pyrrolidinebutyric acid t-butyl ester as a colourless foam. MS: 549 (M+H)+ 505 mg (0.9 mmol) of the above t-butyl ester are stirred at room temperature for 3 hours in 10 ml of 2N hydrochloric acid/acetic acid. Thereafter, the reaction mixture is evaporated under reduced pressure, whereby (aRS.2R)-a-benzyl-2-[[(S)-2-f(benzyloxy)carbonyl]-1--pyrrolidinyl]carbonyl]-ir-oxo-l-pyrrolidinebutyric acid is obtained as a colourless foam. MS: 493 (M+H)+. The (S)-a-amino-N-[(IS.2S.4S)-1-(cyclohexylmethyl)--2-hydroxy-4-isopropylhexyl]imidazole-4-propionamide used as the starting material was prepared as follows: 50 mg of (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4--propionamide are dissolved in 3 ml of methanol and hydrogenated at room temperature for 3 hours at normal pressure in the presence of 7 mg of palladium-on-carbon. Thereafter, the catalyst is filtered off and rinsed with 25 methanol. The alcoholic solution is then evaporated under reduced pressure, whereby (S)-a-amino-N-f(1S.2S,4S)-1--(cyclohexylmethyl)-2 -hydroxy-4-isopropylhexyl]imidazole--4-propionamide is obtained as a colourless foam. MS: 393 (M+H)+. Example 33 The following compounds were manufactured in an analogous manner to that described in Example 1: 35 _ From (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl- methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and (aRS.2R)-a-benzyl-2- 226395 10 15 20 25 30 35 - 89 - -[[(S) -2-[(benzyloxy)carbonyl]-l-pyrrolidinyl]-carbonyl]-Y-oxo-l-pyrrolidinebutyric acid the l-[l-[(RS)-3-[[(S)-l-[[(IS.2S.4S)-1(cyclohexylmethyl )-2-hydroxy-4-isopropy1-5-hexenyl]carbamoyl]--2-imidazo1-4-ylethy1]carbamoyl]-4-phenylbutyryl]--D-prolyl]-L-proline benzyl ester as a 1:1 epimer mixture. MS: 865 (M+H)+; from (S)-a-amino-N-[(IS.2S,4S)-l-(eyelohexy1-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole--4-propionamide and N-(t-butoxycarbonyl)-N-[2--[(RS)-3-carboxy-4-phenylbutyramido]ethyl]glycine t-butyl ester the two epimeric compounds N-(t-butoxycarbonyl)-[2-[(R and S)-3-[[(S)-l--[[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]-4-phenylbutyramido]ethyl]-glycine t-butyl ester. MS: 837 (M+H)+; from (S)-a-amino-N-[(lS.2S,4S)-l-(cyclohexyl-methy1)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and (R)-a-[[[2-hydroxy-l--(hydroxymethyl)-l-methyl]carbamoyl]methyl]hydrocinnamic acid the (S)-N-[(lS.2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-a--[(R)-a-[[[2-hydroxy-l-(hydroxymethyl)-l-methyl-ethy1]carbamoyl]methyl]hydrocinnamamido]imidazole--4-propionamide. MS: 668 (M+H)+; from (S)-a-amino-N-[(lS.2S,4S)-l-(cyclohexyl-methy1)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and 5-[(RS)-3-carboxy-4-phenyl-butyramido]valeric acid t-butyl ester the t-butyl 5-[(RS)-3-[[(S)-l"[[(IS.2S.4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropy1-5-hexenyl]carbamoyl]--2-imidazo1-4-ylethy1]carbamoy1]-4-phenylbutyr-amido]valerate, MS: 736 (M+H)+; 1 2 1 NO]/19^1 * | v' 10 15 20 25 30 35 22 6 3 9 5 - 90 - from (S)-a-amino-N-[(IS.2S,4S)-l(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole -4-propionamide and 3-carboxy-4-phenylbutyryl-L--proline t-butyl ester the l-[(RS)-3-[[(S)-l--[[(IS,2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]-4-phenylbutyryl]-L-proline t-butyl ester, MS: 734 (M+H)+; from (S)-a-amino-N-f(lS,2S,4S)-l(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole -4-propionamide and (RS)-2-benzylmalonic acid 9 monomethyl ester the methyl (RS)-a-[[(S)-l--[[(IS,2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]hydrocinnamate as a 1:1 mixture of the two epimers, MS: 580 (M+); from (S)-a-amino-N-f(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole -4-propionamide and 3-(RS)-ethoxycarbonyl-4-(l--naphthyl)butyric acid6 the ethyl (RS)-a-— 11C(S) — 1—[C(IS.2S,4S)-l-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-carbamoy1]-2--imidazol-4-ylethyl]carbamoyl]methyl]-l--naphthalenepropionate as a 1:1 mixture of the two epimers, MS 659 (M+H)+; from (S)-a-amino-N-f(IS,2S,4S)-l-(cyclohexylmethyl) -2-hydroxy-4-isopropy1-5-hexenyl]imidazole -4-propionamide and (RS)-[(4-benzyl-4--piperidinyl)carbamoyl]imidazole-4-propionic acid the (RS)-a-(l-benzyl-4-piperidinyl)-N-[(S)-l--[[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]imidazole-4-propionamide as a 1:1 mixture of the two epimers. MS: 729 (M+H)+: 9 F: Texier et al.. Tetrahedron, 1974, 3185, 6 EPA 0.181.110 22 6 3 9 5 10 15 20 25 30 35 - 91 - from (S)-a-amino-N-f(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide and 2-(RS)-benzyl-3--morpholinocarbonylpropionic acid and subsequent chromatographic separation of the two epimers the less polar (S)-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexeny1]-a-[(S)--a-[(morpholinocarbony1)methyl]hydrocinnamamido]-imidazole-4-propionamide. MS: 650 (M+H)+, and the more polar (S)-N-[(IS.2S.4S)-1-(cyclohexylmethyl ) -2-hydr oxy-4- isopr opy 1-5-hexenyl ] -a- [ (R)--a-[(morpho1inocarbony1)methyl]hydrocinnamamido]-imidazole-4-propionamide, MS: 650 (M+H)+. The acids used as starting materials were prepared as follows: N-(t-Butoxvcarbonvl)-N-T2-(RS)-3-carboxy-4-phenyl-butvramidoethyl1 glycine t-butvl ester 0.84 g (2.4 mmol) of N-(t-butoxycarbonyl)-N-(2-benzyl-oxycarbonylaminoethyl)glycine10 is suspended in 5 ml of toluene and heated to 80°. To the clear solution obtained in this manner there are added dropwise within 20 minutes 1.96 g of N.N-dimethylformamide di-t-butyl acetal. After completion of the addition the reaction mixture is stirred at 80° for 30 minutes, then cooled and washed in succession with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and evaporated under reduced pressure, whereby N-(t-butoxy-carbony1)-N-(2-benzyloxycarbonylaminoethyl)glycine t-butyl ester is obtained as a colourless oil. MS: 409 (M+H)+. 0.78 g (1.9 mmol) of N-(t-butoxycarbonyl)-N-(2-benzyl-oxycarbonylaminoethyl)glycine t-butyl ester is dissolved 10 U.S. Patent Specification 4.145.337 22 6 3 9 5 10 15 - 92 - in 20 ml of methanol and hydrogenated at pH 4.5 in the presence of 0.1 g of palladium-on-carbon. The pH value is held constant by means of methanol/hydrochloric acid. After completion of the hydrogen uptake the catalyst is filtered off. the filtrate is evaporated and the residue is dissolved in methylene chloride and washed with saturated sodium carbonate solution. After drying the organic phase over sodium sulphate and evaporation under reduced pressure N-(t-butoxycarbonyl)-2-(2-aminoethyl)~ glycine t-butyl ester is obtained in the form of an oil. NMR (250 MHZ. TMS. CDC13>: 6 1.44. 1.47 (2XS.18H) 2.83 (S.2H) 3.36 (S.2H). 3.79. 3.87 (2XS.2H). Condensation of 3-ethoxycarbonyl-4-phenylbutyric acid with N-(t-butoxycarbonyl)-2-(2-aminoethyl)glycine t-butyl ester yields N-(t-butoxycarbonyl)-N-[2-[(RS)-3-(ethoxy-carbonyl)-4-phenylbutyramido]ethyl]glycine t-butyl ester 20 [MS: 492 (M)+] which, in turn, is hydrolyzed with IN sodium hydroxide solution in ethanol at 50° to give the desired acid. N-(t-butoxycarbonyl)-N-[2-[(RS)-3-carboxy-4--phenylbutyramido]ethyl]glycine t-butyl ester. MS: 408 (M-C4H8)+. (R)-g-r T r2-Hvdroxv-l-(hydroxvmethyl)-l-methyll-carbamoyllmethyl!hydrocinnamic acid 3-Ethoxycarbonyl-4-phenylbutyric acid11 and 2-amino--2-methyl-l,3-propanediol are condensed at room temperature in the presence of EDC and HOBT in dimethyl-formamide. whereby there is obtained (RS)-a-[[[2--hydroxy-l-(hydroxymethyl)-l-methyl]carbamoyl]methyl]hydrocinnamic acid ethyl ester, MS: 324 (M+H)+. 35 50 mg of a-chymotrypsin are added to a suspension of 0.54 g (1.67 mmol) of (RS)-a-[[[2-hydroxy-l-(hydroxy-methyl)-l-methyl]carbamoyl]methyl]hydrocinnamic acid ethyl 25 30 11 W. G. Kofron and L. G. Wideman. J. Org. Chem. 32. 555 (1972) 22 6 3 9 5 10 15 - 93 - ester in 15 ml of water, whereby the pH value is held at 7.1 by adding 0.1N sodium hydroxide solution (temperature 25°). After 18 hours 9 ml of 0.1N sodium hydroxide solution have been consumed and the reaction mixture is extracted with ether. The aqueous phase is adjusted to pH 4 with IN hydrochloric acid and subsequently evaporated under reduced pressure. The residue is digested with ethyl acetate. The organic phase is evaporated under reduced pressure and the residue is flash chromatographed on silica gel with a 9:1 mixture of methylene chloride and methanol, whereby (R)-a-[[[2-hydroxy-l-(hydroxymethyl)--l-methyl]carbamoyl]methyl]hydrocinnamic acid is obtained as a colourless foam, MS: 264 (M-CH^OH)^. 5-r(RS)-3-Carboxy-4-phenylbutyramido1valeric acid t-butvl ester 3-Ethoxycarbonyl-4-phenybutyric acid and 5-amino-20 12 valeric acid t-butyl ester are condensed in the presence of EDC and HOBT in dimethylformamide to give 5-[(RS)-3-(ethoxycarbony1)-4-phenylbutyramido]valeric acid t-butyl ester. MS: 392 (M+H)+. Saponification of this ester with IN sodium hydroxide solution in ethanol at 50° yields 5-[(RS)-3-carboxy-4-phenylbutyramido]valeric acid t-butyl ester. MS: 307 (M-C4Hg)+ 3-Carboxy-4-phenvlbutyrvl-L-proline t-butvl ester The synthesis of 3-carboxy-4-phenylbutyryl-L-proline t-butyl ester [MS: 361 (M)+] by condensing 3-ethoxy-carbonyl-4-phenylbutyric acid and L-proline t-butyl ester to give 3-ethoxycarbonyl-4-phenylbutyryl-L-proline t-butyl ester [MS: 389 (M)+] and subsequently saponifying of this is effected analogously to the preparation of 2-(RS)--benzyl-3-morpholinocarbonylpropionic acid described hereinafter. 25 30 35 12 J.H.C. Nayler et al., J. Med. Chem. 20, 1445 (1977) 22 6 3 9 5 10 15 - 94 - (RS)-T(4-Benzy1-4-piperidinyl)carbamoyl1imidazole-4--propioriic acid 2 g (10 mmol) of (RS)-(imidazo1-4-ylmethy1)maIonic acid monomethyl ester (prepared according to a generally known procedure from malonic acid methyl ester by alkylation with chloromethylimidazole and subsequent saponification) and 1.91 g (10 mmol) of 4-amino-benzyl-piperidine are stirred at room temperature for 72 hours with 1.91 g (10 mmol) of EDC in 100 ml of dimethyl-formamide. Thereafter, the reaction solution is evaporated under reduced pressure and the residue is dissolved in 100 ml of methylene chloride and washed with 30 ml of water. The organic phase is then dried over sodium sulphate and evaporated to dryness. The residue is digested with ether and thereafter filtered off. whereby (RS)-[(4-benzy1-4-piperidinyl)carbamoyl]imidazole-4--propionic acid methyl ester is obtained as a colourless powder. MS: 370 (M)+. 371 mg (1 mmol) of the above methyl ester are dissolved in 10 ml of a 1:1 mixture of methanol and water and stirred at room temperature for 24 hours with 1 ml of IN potassium hydroxide in methanol. Thereafter, the reaction solution is evaporated under reduced pressure, the residue is dissolved in water and washed with ether. The aqueous phase is then acidified with 1 mol equivalent of hydrochloric acid and evaporated under reduced pressure, whereby (RS)-[(4-benzyl-4-piperidinyl)-carbamoyl]imidazole-4-propionic acid is obtained as a colourless oil. MS: 312 (M-C02)+. 2-(RS)-Benzy1-3-morpholinocarbonvlpropionic acid 35 1.0 g (4.2 mmol) of 3-ethoxycarbonyl-4-phenylbutyric acid is dissolved in 25 ml of dimethylformamide and treated with 0.37 g (4.2 mmol) of morpholine. 0.81 g 20 25 30 22 6 3 9 5 - 95 - (4.2 mmol) of EDC and 1.3 g (8.4 mmol) of HOBT and stirred ^ at room temperature for 48 hours. Thereafter, the reaction solution is evaporated in a high vacuum and the residue is dissolved in ethyl acetate and washed in succession with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is then dried 10 over sodium sulphate and evaporated under reduced pressure and the residue is chromatographed on silica gel using a 95:5 mixture of methylene chloride and ethanol. whereby 2-(RS)-l-benzyl-3-morpholinocarbonylpropionic acid ethyl ester is obtained as a colourless oil, MS: 305 (M) + . 15 20 25 30 35 0.42 g (1.4 mmol) of the above ester is dissolved in 2 ml of ethanol and treated with 2.1 ml (1.5 mol equivalents) of IN sodium hydroxide solution. The reaction solution is then stirred at 50° for 4 hours and the residue is dissolved in water and washed with ether. The aqueous phase is acidified with 2.3 ml of IN hydrochloric acid and extracted with methylene chloride. The organic extracts are dried over sodium sulphate and evaporated under reduced pressure, whereby 2-(RS)-benzyl-3--morpholinocarbonylpropionic acid is obtained as a colourless oil which is used directly in the next step, MS: 277 (M)+. Example 34 100 mg (0.13 mmol) of t-butoxycarbonyl [2-[(RS)-3--[[(S)-1-[[(lS,2S,4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]-4-phenylbutyramido]ethyl]glycine t-butyl ester are dissolved in 2 ml of acetic acid and stirred at room temperature for 3 hours with 4 ml of IN hydrochloric acid/ acetic acid. Thereafter, the reaction mixture is evaporated under reduced pressure and the residue is 22 6 3 9 5 10 15 20 25 30 35 - 96 - digested with ether and filtered off. whereby N-[2-[(RS)--3-[[(S)-l-r[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]-4-phenylbutyramido]ethyl]glycine dihydro-chloride is obtained as a powder. MS: 681 (M+H)+. Example 35 54 mg Of t-butyl 5-[(RS)-3-[[(S)-l-{[(IS.2S.4S)--1(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-4-phenyl butyramido]valerate are dissolved in 1 ml of acetic acid and treated at room temperature with 2 ml of hydrochloric acid/acetic acid (1.5N) and stirred at this temperature for 2.5 hours. The reaction mixture is then evaporated under reduced pressure and the residue is digested with ether and filtered off. whereby 5-[(RS)-3-[[(S)-l--[[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5 -hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-4--phenylbutyramido]valeric acid hydrochloride is obtained as a colourless powder. MS: 680 (M+H)*. Example 36 The following compounds were manufactured in an analogous manner to that described in Example 27: From (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole -4-propionamide and (RS)-2-benzyl-6.6-dimethyl-4--oxoheptanoic acid the (S)-N-[(IS.2S.4S)-1(cyclohexylmethyl )-2-hydroxy-4-isopropy1-5-hexenyl]-a--[(RS)-a-(4.4-dimethy1-2-oxopentyl)hydrocinnamamido] imidazole-4-propionamide. MS: 635 (M+H)+; 22 6 39 5 - 97 - 10 15 20 25 30 35 from (S)-a-amino-N-[(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and (RS)-a-benzyl-y-oxo--cyclohexanebutyric acid and subsequent separation of the two epimers the less polar (S)-a-[(S)-a-r(cyclohexylcarbonyl)methyl]hydrocinnamamido ]-N-[(1S.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propion-amide [MS: 647 (M+H)+] and the more polar (S)-a-[(R)-a-[(eyelohexylcarbony1)methyl]hydrocinnamamido ]-N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropy1-5-hexenyl]imidazole-4-propionamide. MS: 647 (M+H)+; from (S)-a-amino-N-[(IS,2S,4S)-1-(eyelohexy1-methy1)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole--4-propionamide and (RS)-a-benzyl-Y-oxo--eyclopentanebutanoie acid the (S)-N-[(IS,2S,4S)--1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]-a-[(RS-a-[(eyelopentyicarbonyl)-methyl]hydrocinnamamido]imidazole-4-propionamide. MS: 633 (M+H)+; from (S)-a-amino-N-(lS,2S,4S)-1-(eyelohexy1-methyl)-2-hydroxy-4-isopropy1-5-hexeny1]imidazole--4-propionamide and (RS)-2-benzyl-5,5-dimethyl-4--oxohexanoie acid the (S)-a-[(RS)-2-benzyl-5,5--dimethyl-4-oxohexananamido]-N-[(1S.2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide. MS: 621 (M+H)+; from (S)-a-amino-N-[(IS.2S.4S)-1-(eyelohexy1-methyl)-2-hydroxy-4-isopropy1-5-hexeny1]imidazole--4-propionamide and (R)-2-benzyl-5.5-dimethyl-4--oxohexanoic acid the (S)-a-[(R)-2-benzyl-5.5--dimethy1-4-oxohexanamido]-N[(IS.2S.4S)-1-(cyclohexylmethyl) -2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. MS: 621 (M+H)+; 22 6 3 9 5 10 - 98 - from (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and (aRS,S)-a-benzyl-l--(benzyloxycarbonyl)-y-oxo-2-pyrrolidinebutyric acid the benzyl (S)-2-[[(RS)-a-[[(S)-l--[[(1S.2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethy1]carbamoyl]phenethy1]acetyl]-l-pyrrolidine-carboxylate. MS: 768 (M+H)+. The acids used as the starting materials were prepared as follows in analogy to the preparation of 2-(RS)-benzyl-^ -4-(4-chlorophenyl)-4-oxobutyric acid (see Example 27): From l-chloro-4,4-dimethyl-2-pentanone, which in turn was prepared in a manner known per se from 3.3-dimethylbutyryl chloride by reaction with diazomethane and hydrogen chloride, and benzylmalonic acid diethyl ether the (RS)-2-benzyl-6.6--dimethyl-4-oxoheptanoic acid; from bromoacetylcyclohexane13 and benzylmalonic acid diethyl ester the (RS)-a-benzyl-y-oxo- cyclohexanebutyric acid; 25 13 from bromoacetylcyclopentane and benzylmalonic acid diethyl ester the (RS)-a-benzyl--y-oxocyclopentanebutyric acid; from N-benzyloxycarbonyl-prolyl-bromomethane. which was prepared in analogy to the preparation 30 of N-t-butoxycarbonyl-prolyl-bromomethane14. and benzylmalonic acid diethyl ester the (aRS.S)-a-benzyl-1-(benzyloxcarbonyl)-y-oxo--2-pyrrolidinebutyric acid. 35 The (RS)-2-benzyl-5.5-dimethyl-4-oxohexanoic acid and the enantiomeric (R)-2-benzyl-5.5-dimethyl-4-oxohexanoic 20 13 M. Gaudry and A. Marquet. Tetrahedron. 1970. 5611 14 EPA 0.129.163 22 6 3 9 5 10 - 99 - acid which are likewise used as starting materials are known from European Patent Publication 0 184 550. Example 37 The following compounds were manufactured by catalytically hydrogenating the corresponding olefins in an analogous manner to that described in Example 2: (S)-N-[(IS.2S.4S)-1-(Cyclohexylmethyl)-4-ethyl-2--hydroxy-5-methylhexyl]-a-[(R)-a-[(morpholino-carbonyl)-methyl]hydrocinnamamido]imidazole-4--propionamide. MS: 652 (M+H)+; (S)-a-[(R)-a-(3.3-dimethyl-2-oxobutyl)hydro-cinnamamido]-N-[(IS,2S.4S)-1-(cyclohexylmethyl)-2--hydroxy-4-isopropylhexyl]imidazole-4-propionamide, MS: 623 (M+H)+; (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropylhexyl]-a-[[[[(R)-a-2-hydroxy-l--(hydroxymethyl)-l-methylethyl]carbamoyl]methyl]-hydrocinnamamido]imidazole-4-propionamide. MS: 620 (M+H)+; N-[(S) — 1—[[(IS,2S.4S)-1-(cyclohexylmethyl)-2--hydroxy-4-isopropylhexy1]carbamoyl]-2-imidazo1-4--ylethyl]-y-oxo-a-(1-naphthylmethyl)-4--morpholinebutyramide. MS: 702 (M+H)+. 15 20 30 Example 38 90 mg (0.23 mmol) of (S)-a-amino-N-[(1S.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide and 0.047 ml of Hiinig base in 2 ml of acetonitrile are treated dropwise at room 35 temperature with a solution of 60.7 mg of (S)-a-[(3.3- -dimethylbutyryl)oxy]hydrocinnamic acid and 101 mg of BOP in 5 ml of acetonitrile. The mixture is stirred at room 22 6 3 9 5 10 15 20 25 30 35 - 100 - temperature for 4 hours, subsequently poured into 2N sodium bicarbonate solution and extracted with methylene chloride. The organic phase is washed with ammonium chloride solution and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is chromatographed on silica gel. whereby after elution with a 20:1 mixture of methylene chloride and methanol there are obtained 50 mg (34%) of (S)-a-[[(S)-l--[[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5 -hexenyl]carbamoy1]-2-imidazo1-4-ylethyl]carbamoyl]-phenethyl 3.3-dimethylbutyrate as a yellow oil. MS: 637 (M+H)+ The (S)-a-[(3.3-dimethylbutyryl)oxy]hydrocinnamic acid used as the starting material was prepared as follows 2.1 g (8.2 mmol) of (S)-2-hydroxy-3-phenylpropionic 15 acid benyl ester and 1.24 ml of triethylamine in 100 ml of methylene chloride are treated dropwise at room temperature within 2 hours with 1.26 ml of t-butylacetyl chloride. Thereafter, the reaction mixture is stirred at 40® for 6 hours. Subsequently, the mixture is poured into water and extracted with methylene chloride. After drying over sodium sulphate the solvent is removed under reduced pressure and the crude product is purified by flash chromatography on silica gel with a 1:3 mixture of ether and petroleum ether, whereby there are obtained 1.4 g (48%) of (S)-a-[(2,3-dimethylbutyryl)oxy]hydrocinnamic acid benzyl ester. MS: 238 [M-(CH3)3CCH2COOH]+ The 1.4 g (3.95 mmol) of the benzyl ester obtained above are dissolved in 80 ml of ethanol and hydrogenated at room temperature for 2 hours and in the presence of 0.4 g of palladium-on-carbon. Filtration of the catalyst and evaporation of the solvent under reduced pressure 15 Isv. Acad. Navk SSR. Set. Khim. 1966(3), 519 22 6 3 9 5 - 101 - yields 1 g (96%) of (S)-a-[(3,3-dimethylbutyl)oxy]hydro-cinnamic acid as a colourless oil which is used directly in the next step. Example 39 100 mg (0.3 94 mmol) of (aS./3S)-fl-amino-a-[ (S)-2--isopropyl-3-butenyl]cyclohexanepropanol in a mixture of 3.5 ml of dimethylformamide and 7 ml of acetonitrile are treated at room temperature with 0.079 ml of Hiinig base. Thereafter. 174 mg of BOP and 150 mg (0.394 mmol) of (S)-a-(dibenzylacetoxy)imidazole-4-propionic acid are added thereto and the solution is stirred at room temperature for 6 hours. Thereafter, the mixture is diluted with 60 ml of ethyl acetate and washed with IN hydrochloric acid and sodium bicarbonate solution. The organic phase is then dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 179 mg of (S)-l-[[(IS,2S.4S)-l-(cyclohexylmethyl )-2-hydroxy-4 -isopropyl-5-hexenyl]carbamoyl]-2--(imidazol-4-yl)ethyldibenzylacetate as an amorphous powder. MS: 596 (M-0H)+ The (S)-a-(dibenzylacetoxy)imidazole-4-propionic acid used above as the starting material was prepared as follows: Dry hydrochloric acid gas is conducted at 0° during 3 minutes through a suspension of 2.5 g of a-hydroxy-imidazolepropionic acid16 in 80 ml of benzyl alcohol and the solution obtained is subsequently left to stand at room temperature for 12-20 hours. Thereafter, the excess 16 C.E. Baker and A. Merster. JACS 73. 1336 22 6 3 9 5 10 15 20 25 30 - 102 - benzyl alcohol is distilled off in a high vacuum and the cesidue is dissolved in methylene chloride and washed with sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 3.5 g (89%) of (S)-a-hydroxyimidazolepropionic acid benzyl ester as a yellow oil. MS: 246 (M)+ 6.19 ml (48.3 mmol) of benzenesulphonyl chloride are added dropwise at -5° to 10.53 g (43.8 mmol) of dibenzyl-acetic acid in 50 ml of pyridine and the reaction solution is stirred at room temperature for 30 minutes. Subsequently, a solution of 6 g (24.4 mmol) of (S)-a--hydroxyimidazolepropionic acid benzyl ester in 5 ml of pyridine is added dropwise at -5° and the solution is stirred firstly at 0° for 2 hours and thereafter at room temperature for a further 2 hours. The reaction mixture is then poured on to 3N hydrochloric acid/ice and extracted with ethyl acetate. The organic extracts are thereafter washed with 2N sodium bicarbonate solution, dried over sodium sulphate and evaporated under reduced pressure. The residue is flash chromatographed on silica gel using a 15:1 mixture of methylene chloride and ethyl acetate, whereby there are obtained 6.35 g (47%) of a 1:1 mixture of (S)-a-dibenzylacetoxy-N-(phenylsulphonyl)imidazole--4-propionic acid benzyl ester and (S)-a.N-bis(dibenzylacetoxy) imidazole-4 -propionic acid benzyl ester as a yellow oil which is used in the next step without further purification. 35 95 ml of a 0.3N hydrochloric acid/methanol solution are added to 5.74 g (9.4 mmol) of the above mixture in 22 6 3 9 5 10 15 - 103 - 25 ml of methanol and sticred at room temperature for 2 hours. Thereafter, the mixture is poured into ice/sodium bicarbonate and the product is extracted with ethyl acetate, dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel. whereby there are obtained 3.2 g (70%) of (S)-a-(dibenzylacetoxy)-imidazole-4-propionic acid benzyl ester. MS = 468 (M)+ 3.2 g (6.83 mmol) of (S)-a-(dibenzylacetoxy)-imidazole-4-propionic acid benzyl ester in 150 ml of methanol are hydrogenated at room temperature for 2 hours in the presence of 660 mg of palladium-on-carbon. Thereafter. the catalyst is filtered off and the filter residue is washed several times with a 1:1 mixture of methylene chloride and methanol. Thereafter, the solution is concentrated under reduced pressure until crystallization occurs. Recrystallization of the crystallizate from methylene chloride/methanol yields 2.5 g (96%) of (S)-a--(dibenzylacetoxy)imidazole-4-propionic acid, melting point 210°. Example 40 442 mg (1 mmol) of BOP and 0.204 ml of Htinig base are added to 236.2 mg (1 mmol) of R-(+)-a-benzylsuccinic 30 . 17 acid monoethyl ester and 390.6 mg (1 mmol) of (S)-a- -amino-N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4- -sopropyl-5-hexenyl]imidazole-4-propionamide in aceto- nitrile and the solution obtained is stirred at room temperature for 20 hours. Thereafter, the reaction mixture is poured on to IN hydrochloric acid/ice and extracted with ethyl acetate. The organic extracts are washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue is chromatographed on silica 20 25 35 17 S.G. Cohen, A. Milovanovic, JACS 90, 3495 (1968) 22 6 3 9 5 15 - 104 - gel with a 10:1 mixture of methylene chloride and methanol 5 as the eluting agent, whereby there are obtained 465 mg (76%) of ethyl (R)-3-[[(S)-l-[[(IS,2S,4S)-1-(cyclohexylmethyl) -2-hydr oxy-4- isopr opy 1-5-hexenyl] car bamoyl] -2--imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate as an amorphous powder. 10 MS: 609 (M+H)+ Example 41 181 mg (0.404 mmol) of BOP and 0.083 ml of Htinig base are added to 66.5 mg (0.404 mmol) of (S)-(+)-a-methyl- 18 hydrocinnamic acid and 157 mg (0.404 mmol) of (S)-a--amino-N-[(IS,2S» 4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide in 10 ml of acetonitrile and stirred at room temperature for 16 hours. Thereafter, the reaction solution is poured into IN hydrochloric acid/ice and extracted with ethyl acetate. The organic extracts are washed with sodium bicarbonate solution and dried over sodium sulphate. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 136 mg (63%) of N-[(IS.2S)-1-(eyelohexylmethyl)--2-hydroxy-4-isopropy1-5-hexenyl]-a-[(S)-a-methylhydro-cinnamamido]imidazole-4-propionamide as an amorphous solid. MS: 537 (M+H)+ Example 42 135 mg of BOP and 0.062 ml of HUnig base are added to 73 mg of a-methylcinnamic acid and 117.75 mg of (S)-a--amino-N-[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide in 5 ml of 20 25 30 35 18 A.W. Schrecker J. Org. Chem. 22., 33 (1957) 2 2 6 3 9 5 10 15 20 30 35 - 105 - acetonitrile and stirred at room temperature for 20 hours. Thereafter, the reaction solution is poured on to 3N hydrochloric acid/ice and extracted with ethyl acetate. The organic phase is washed with 2N sodium carbonate solution and dried over sodium sulphate. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 100 mg of N-[[(lS,2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropy1-5-hexeny1]-a-[a-methylcinnamoyl]-amino]-imidazole-4-propionamide as an amorphous solid. MS: 535 (M+H)+ Example 43 106 mg (0.404 mmol) of t-butoxycarbonyl-a.J3-dehydro-19 phenylalanine and 157 mg of (S)-a-amino-N- -[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide in 10 ml of acetonitrile are treated with 181 mg of BOP and 0.083 ml of Hiinig base and subsequently stirred at room temperature for 16 hours. Thereafter, the solution obtained is poured on to IN hydrochloric acid/ice, extracted with ethyl acetate. washed with 2N sodium carbonate solution, dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel with a 20:1 mixture of methylene chloride and methanol, whereby there are obtained 144 mg (54%) of (S)-a-[a--(t-butoxycarbonylamino)cinnamoyl]-N-[(IS,2S,4S)-1-(eyelohexy lmethyl)-2-hydroxy-4-isopropy1-5-hexeny1]imidazole-4- -propionamide as an amorphous solid. MS: 636 (M+H)+ 19 H. Poisel, Chem. Ber. 110, 948 (1977) 22 6 3 9 5 10 15 20 25 30 35 - 106 -Example 44 100 mg (0.256 mmol) of (S)-a-amino-N-[(1S,2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-imidazole-4-propionamide and 0.052 ml of Hiinig base in 2 ml of acetonitrile are treated with 92 mg of (S)-a--(diphenylacetoxy)hydrocinnamic acid and 113 mg of BOP in 2 ml of acetonitrile and stirred at room temperature for 12 hours. The reaction solution is then poured on to IN hydrochloric acid/ice. extracted with ethyl acetate, the organic phase is washed with sodium carbonate solution, dried over sodium sulphate and finally the solvent is removed under reduced pressure. The residue is chromatographed on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 130 mg of (S)-a-[[(S)-l-[[(IS.2S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]phenethyl dibenzylacetate in the form of an amorphous solid. MS: 73 3 (M+H)+ The (S)-a-(diphenylacetoxy)hydrocinnamic acid used as the starting material was prepared as follows: 1.06 g (5 mmol) of diphenylacetic acid in 5 ml of pyridine are treated dropwise at -5° with 0.833 ml (6.5 mmol) of benzenesulphonyl chloride and the solution is subsequently stirred at room temperature for 30 minutes. Then, 1.28 g (5 mmol) of (S)-2-hydroxy-3- 20 -phenylpropionic acid benzyl ester in 5 ml of pyridine are added and the mixture is stirred at 0-10° for 2 hours and at room temperature for a further 2 hours. The reaction solution is treated with water and extracted with ethyl acetate. The organic phases are washed with IN hydrochloric acid and sodium bicarbonate solution and dried over sodium sulphate. The solvent is evaporated 20 Isv. Acad. Navk SSR, Ser. Khim. 1966(3), 519 22 6 3 9 10 15 20 30 - 107 - under reduced pressure and the residue is flash chromatographed on silica gel with a 4:1 mixture of petroleum ether/ether, whereby there are obtained 1.8 g (80%) of benzyl (S)-a-(diphenylacetoxy)hydrocinnamate in the form of a yellow oil. MS: 359 (M-benzyl)+ The obtained 1.8 g of the above-named benzyl ester are dissolved in 180 ml of acetic acid, treated with 300 mg of palladium-on-carbon and hydrogenated at room temperature until the theoretical amount of hydrogen has been taken up (approximately 2 hours). The catalyst is then filtered off and the solvent is removed under reduced pressure, whereby the desired acid begins to crystallize out slowly. Filtration of the separated crystals yields 1.3 g (90%) of (S)-a-(diphenylacetoxy)hydrocinnamic acid. MS: no mol peak 212 (diphenylacetic acid)+ 167 (diphenylmethyl)+ Example 45 25 100 mg of (aS.flS)-B-amino-a-[(S)-2-isopropyl-3- -butenyl]cyclohexanepropanol in 20 ml of acetonitrile are treated with 0.080 ml of Htinig base. 174 mg of BOP and 140 mg of (S)-3-carbamoyl-2-(dibenzylacetoxy)propionic acid and stirred at room temperature for 12 hours. Thereafter, the reaction solution is poured on to IN hydrochloric acid/ice. extracted with ethyl acetate, the extracts are washed with sodium carbonate solution and finally dried over sodium sulphate. The solvent is then removed under reduced pressure and the residue is O C chromatographed on silica gel with a 20:1 mixture of methylene chloride and methanol, whereby there are obtained 142 mg (60%) of (S)-2-carbamoyl-l-[[(IS.2S.4S)-1- 22 6 3 9 5 10 15 - 108 - -(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]ethyl dibenzylacetate in the form of a resin. MS: 591 (M+H)+ The (S)-3-carbamoyl-2-(dibenzylacetoxy)propionic acid used as the starting material was prepared as follows: 480 mg (2 mmol) of dibenzylacetic acid in 3 ml of pyridine are treated at -5° with 0.34 ml of benzene-sulphonyl chloride and subsequently stirred at room temperature for 30 minutes. Thereafter, 447 mg (2 mmol) of benzyl (S)-B-malamidate are added and the reaction solution is stirred firstly at 0° for 2 hours and then at room temperature for a further 2 hours. The reaction solution is then diluted with 100 ml of ethyl acetate, dilute hydrochloric acid is added and the two phases obtained are separated. The organic phase is washed with sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure. Chromatography of the residue on silica gel using a 4:1 mixture of methylene chloride and ethyl acetate as the eluting agent yields 539 mg (59%) of benzyl (S)-3-carbamoyl-2-(dibenzyl-acetoxy)propionate in the form of a yellow oil. 25 MS: 354 (M-benzyl)+ 520 mg of the above-named benzyl ester in 5 ml of methanol are hydrogenated at room temperature for two hours in the presence of 100 mg of palladium-on-carbon. Thereafter, the catalyst is filtered off and the solvent is removed under reduced pressure, whereby there are obtained 370 mg (90%) of (S)-3-carbamoyl-2-(dibenzyl-acetoxy)propionic acid as a white solid. MS: 338 (M-NH_)+ 35 20 30 22 6 39 10 15 20 30 - 109 -Example 4 6 100 mg (0.256 mmol) of (S)-a-amino-N-[(1S.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide and 0.052 ml of Hiinig base in 2 ml of acetonitrile are treated at room temperature with 100 mg of N-(dibenzylcarbamoyl)-3-phenyl-L-alanine and 113 mg of BOP and subsequently stirred at room temperature for 12 hours. Thereafter, the reaction solution is poured on to IN hydrochloric acid/ice, extracted with ethyl acetate, the extracts are dried over sodium sulphate and the solvent is removed under reduced pressure. Chromatography of the residue on silica gel using a 10:1 mixture of methylene chloride and methanol as the eluting agent yields 130 mg of 1.l-dibenzyl-3-[(S)-a-[[(S)-l--[[(IS,2S.4S)-1 -(cyclohexylmethyl)-2-hydroxy-4-isopropyl--5-hexeny1]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-phenethyl]urea in the form of an amorphous solid. MS: 761 (M+H)+ The N-(dibenzylcarbamoyl)-3-phenyl-L-alanine used as the starting material was prepared as follows: 25 l g (5.06 mmol) of dibenzylamine and 1.73 ml (10.1 mmol) of Hiinig base in 50 ml of methylene chloride are treated dropwise while cooling with ice with 2.6 ml of phosgene in toluene (20%. 5.06 mmol) and the solution obtained is stirred at 0° for 3 hours. Then, 1.1 g of L-phenylalanine methyl ester are added and the mixture is heated to 40° for 12 hours. Thereafter, the reaction mixture is poured into water, extracted with methylene chloride and the extracts are dried over sodium sulphate. The solvent is then removed under reduced pressure and the 35 residue is chromatographed on silica gel using a 15:1 mixture of methylene chloride and ether as the eluting agent, whereby there are obtained 900 mg (45%) of 22 6 395 10 15 20 30 - 110 - N-(dibenzylcarbamoyl)-3-phenyl-L-alanine methyl ester as a white solid. MS: 402 (M)+ 900 mg (2.23 mmol) of the above-named methyl ester in 20 ml of ethanol are treated with 9 ml of 0.5N sodium hydroxide solution (4.46 mmol) and heated to 40° for 1 hour. Thereafter, the reaction solution is acidified and the product is extracted with methylene chloride. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure, whereby there are obtained 100 mg (92%) of N-(dibenzylcarbamoyl)-3--phenyl-L-alanine as an amorphous solid. MS: 388 (M)+ Example 47 100 mg (0.52 mmol) of (S)-a-amino-N-[(1S,2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-imidazole-4-propionamide and 0.052 ml of Hiinig base in 2 ml of acetonitrile are treated at room temperature with 99 mg of N-(morpholinocarbamoyl)-3-phenyl-L-alanine and 25 113 mg of BOP in 2 ml of acetonitrile and stirred at room temperature for 12 hours. Thereafter, the reaction solution is poured on to IN hydrochloric acid/ice. extracted with ethyl acetate, the organic extracts are dried over sodium sulphate and the solvent is removed under reduced pressure. Thereafter, the residue is chromatographed on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 130 mg (67%) of (S)-N-[(lS,2S.4S)-l-(cyclohexylmethyl )-2-hydroxy-4-isopropy1-5-hexenyl]-a-2-[N-35 -(morpholinocarbamoyl)-3-phenyl-L-alanyl]amino]imidazole-4--propionamide as an amorphous solid. MS: 651 (M+H)+ 22 6 3 9 5 10 15 - Ill - The N-(morpholinocarbamoyl)-3-phenyl-L-alanine used as the starting material was prepared as follows: 3.6 ml of phosgene in toluene (20%, 6.95 mmol) are added dropwise while cooling with ice to 0.6 ml (6.95 mmol) of morpholine and 2.4 ml (13.9 mmol) of Hiinig base in 20 ml of methylene chloride and the solution is stirred at 0° for 3 hours. Thereafter, 1.5 g (6.95 mmol) of phenylalanine methyl ester hydrochloride are added and the reaction solution is stirred at 40° for 12 hours. Subsequently, the reaction solution is poured on to ice and extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. Chromatography of the residue on silica gel using a 2:1 mixture of methylene chloride and ether as the eluting agent yields 400 mg (20%) of N-(morpholino-carbamoyl)-3-phenyl-L-alanine methyl ester in the form of a resin. 20 + MS: 292 (M) 400 mg (1.37 mmol) of the above-mentioned methyl ester in 10 ml of ethanol are treated with 5.5 ml of 0.5N sodium hydroxide solution (2.75 mmol). The reaction mixture is 25 then stirred at 40° for 1 hour, subsequently poured on to 3N hydrochloric acid/ice, extracted with methylene chloride, the organic extracts are dried over sodium sulphate and finally the solvent is removed under reduced pressure. There are thus obtained 210 mg (55%) of N-(morpholinocarbamoyl)-3-phenyl-L-alanine in the form of an amorphous solid. MS: 278 (M)+ Example 48 A solution of 100 mg (0.256 mmol) of (S)-a-amino-N--[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide, 0.052 ml of Hiinig base. 30 35 22 6 3 9 5 10 15 20 25 30 35 - 112 - 113 mg of BOP and 81 mg of N-(t-butoxycarbonyl)-B-pyrazol-21 -1-yl-L-alanine in acetonitrile is stirred at room temperature for 12 hours. Thereafter, the reaction mixture is poured on to IN hydrochloric acid/ice. extracted with ethyl acetate, the extracts are dried over sodium sulphate and the solvent is finally removed under reduced pressure. Chromatography of the residue on silica gel with a 7:1 mixture of methylene chloride and methanol yields 80 mg (50%) of white crystals of t-butyl [(S)-l-[(IS,2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4 -isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoy1-2-pyrazo1-1--ylethyl] carbamate. MS: 628 (M+H)+ Example 49 A solution of 103 mg of N-[[2-(4-biphenyloxy)ethyl]-carbamoyl]-3-phenyl-L-alanine and 113 mg of BOP in acetonitrile is added to 100 mg (0.256 mmol) of (S)-a-amino--N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide 0.052 ml of Hiinig base in 5 ml of acetonitrile and the mixture is subsequently stirred at room temperature for 12 hours. Subsequently, the reaction mixture is poured on to IN hydrochloric acid/ice, extracted with ethyl acetate, the extracts are dried over sodium sulphate and evaporated to dryness under reduced pressure. The crude product is purified by chromatography on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 90 mg (45%) of l-[2-(4-biphenyloxy)ethyl]-3-[(S)--a-[[(S)—1—[[(IS.2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl]urea as an amorphous powder. MS: 777 (M+H)+ 21 L.D. Arnold, T.H. Kalantar, J.C. Vederas, JACS 107, 7105 (1985) 226395 10 15 20 25 30 35 - 113 - The N-[[2-(4-biphenyloxy)ethyl]carbamoyl]- 3-phenyl-L--alanine used as the starting material was prepared as foilows: 4.8 ml of Hiinig base and 7 ml of a 20% phosgene solution in toluene are added at 0° to 3 g (14.06 mmol) of 22 2-(4-biphenyloxy)ethylamine in 100 ml of toluene and the reaction mixture is subsequently stirred at 0° for one hour. Thereafter. 6 g of L-phenylalanine benzyl ester are added and the solution is stirred at 90° for 12 hours. Thereafter, the reaction mixture is worked-up in the usual manner and the crude product is purified by chromatography on silica gel with a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 4.5 g (67%) of N-[[2-(4-biphenyloxy)ethyl]carbamoyl]-3-pheny1-L-alanine benzyl ester. 4.5 g (9.4 mmol) of the above-named benzyl ester in 250 ml of ethanol are hydrogenated at room temperature in the presence of 0.5 g of palladium-on-carbon until the theoretical amount of hydrogen has been taken up. Thereafter, the catalyst is filtered off. the solvent is evaporated under reduced pressure and the residue is recrystallized from ether/methylene chloride/methanol. whereby there are obtained 2.1 g (55%) of N-[[2-(4- -biphenyloxy)ethy1]carbamoyl]-3-pheny1-L-alanine. melting 20 point 175°; [o068g = +8.4° (c = 1%. methanol). Example 50 A solution of 100 mg of (S)-a-[(dibenzylcarbamoyl)-oxy]hydrocinnamic acid and 113 mg of BOP in 2 ml of acetonitrile is added to 100 mg (0.256 mg) of (S)-a-amino-N--[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5- -hexenyl] imidazole-4-propionamide and 0.052 ml of Hiinig »• base in 5 ml of acetonitrile and the mixture is 22 GB Patent Specification 1.501.541 22 6 3 9 5 10 15 20 25 30 35 - 114 - subsequently stirred at room temperature for 12 hours. The working-up is effected in the usual manner. There are thus obtained 150 mg (77%) of (S)-a-[[(S)-l-[[(IS,2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]phenethyl dibenzyl carbamate. MS: 762 (M+H)+ The (S)-a-(dibenzylcarbamoyloxy)hydrocinnamic acid used as the starting material was prepared as follows: 2.23 ml (4.3 mmol) of a 20% phosgene solution in toluene are added dropwise while cooling with ice to 1.0 g (3.9 mmol) of (S)-2-hydroxy-3-phenylpropionic acid and 1.68 ml (3.9 mmol) of Htinig base in 20 ml of tetrahydrofuran and the mixture is subsequently stirred at 0-10° for 1.5 hours. Then. 0.824 ml (4.3 mmol) of dibenzylamine in 20 ml of tetrahydrofuran are added dropwise and the reaction solution is stirred at room temperature for a further 12 hours. Subsequently, the mixture is poured on to ice. neutralized with potassium bicarbonate solution and extracted with ethyl acetate. For purification, the crude product obtained is flash chromatographed on silica gel using a 3:1 mixture of petroleum ether and ether, whereby there are obtained 825 mg (42%) of (S)-a--[(benzyloxy)carbonyl]phenethyl dibenzyl carbamate as a resin. MS: 388 (M-benzyl)+ 0.8 g of the above-described benzyl ester is hydrogenated at room temperature for 2.5 hours in 30 ml of a 4:1 mixture of methanol and ethyl acetate in the presence of 80 mg of palladium-on-carbon. Thereafter, the catalyst is filtered off and the solvent is evaporated under reduced pressure. There are thus obtained 461 mg (73%) of (S)-a-[(dibenzylcarbamoyl)oxy]hydrocinnamic acid in the form of a resin. MS: 389 (M)+ 22 6 39 5 ' 10 15 20 30 35 - 115 -Example 51 A solution of 100 mg of ethyl (R)—3—[[(S)-l--[[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexeny1]carbamoyl]-2-imidazolr4-ylethyl]carbamoyl]-4--phenylbutyrate in 30 ml of methanol is saturated with ammonia for 1-2 minutes and subsequently left to stand at room temperature for 12 hours. Thereafter, the solvent is removed under reduced pressure and the residue is chromatographed on silica gel with 10% methanol in methylene chloride as the eluting agent, whereby there are obtained 63 mg (66%) of (S)-a-[(R)-a-(carbamoyl-methyl)hydrocinnamamido]-N-[(IS,2S,4S)-l-(cyclohexylmethyl) -2-hydroxy-4-isopropy1-5-hexenyl]imidazole-4-propionamide as a resin. MS: 580 (M+H)+ Example 52 A solution of 84.62 mg (0.3 mmol) of t-butoxycarbonyl--a-methyl-D,L-phenylalanine, 135 mg of BOP, 118 mg of (S)-a-amino-N-[(IS,2S,4S)-l-(cyclohexylmethyl)-2-25 -hydroxy-4-isopropy1-5-hexenyl]imidazole-4-propionamide and 0.062 ml of Htinig base is stirred at room temperature for 12 hours. The reaction mixture is thereafter worked-up as described in Example 48, whereby there are obtained 125 mg (64%) of t-butyl [(R or S)-a-[[(S)-l--[[(IS,2S,4S)-1-(eyelohexylmethyl)-2 -hydroxy-4-isopropyl--5-hexeny1]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-a--methylphenethyl] carbamate as an epimer mixture. The two epimers can be separated by chromatography on silica gel with 10% methanol in methylene chloride. The more polar epimer has a Rf value of 0.38, while the less polar has a Rf value of 0.46. MS: 652 (M+H)+ 22 6 3 9 5 10 15 20 25 30 35 - 116 - The t-butoxycarbonyl-a-methyl-D.L-phenylalanine used as the starting material was prepared as follows: 2.44 g (11.16 mmol) of di-t-butyl dicarbonate in 5 ml of t-butyl alcohol are added dropwise at room temperature to 2.0 g (11.16 mmol) of a-methyl-D,L-phenylalanine in 11.16 ml of IN sodium hydroxide solution and 10 ml of t-butyl alcohol and the reaction mixture is subsequently stirred at room temperature overnight. Thereafter, water is added, the mixture is washed with pentane. the aqueous phase is adjusted to pH 2 by the addition of potassium bisulphate solution and extracted with ethyl acetate. The organic phase is then dried over sodium sulphate and concentrated, whereby 1.56 g (50%) of t-butoxycarbonyl--a-methyl-D.L-phenylalanine separate as a white powder which is used directly in the next step. Example 53 A mixture of 100 mg (0.45 mmol) of N-benzyl-3--carbamoyl-D-alanine. 187 mg (0.45 mmol) of (S)-a-amino--N-[(IS.2S.4S)-l-(cyclohexylmethy1)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide. 0.093 ml of Hiinig base and 202 mg of BOP in 10 ml of a 2:1 mixture of acetonitrile and dimethylformamide is stirred at room temperature for 18 hours. Thereafter, the reaction mixture is poured into aqueous ammonium chloride solution. extracted with ethyl acetate, the extracts are washed with sodium carbonate solution, dried over sodium sulphate and evaporated to dryness under reduced pressure. Chromatography of the residue on silica gel with 10% methanol in methylene chloride as the eluting agent yields 87 mg (32%) of (S)-a-[(R)-2-(benzylamino)-3-carbamoylpropionamido]--N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide as a resin. MS: 595 (M+H)+ 22 6 39 5 10 15 20 - 117 - The N-benzyl-3-carbamoyl-D-alanine used as the starting material was prepared as follows: 1.5 g (10 mmol) of D-asparagine hydrate in 5 ml of 2N sodium hydroxide solution are treated with 1.01 ml (10 mmol) of benzaldehyde and the reaction mixture is stirred homogeneously at room temperature for 20 minutes. Subsequently. 114 mg (3 mmol) of sodium borohydride are added portionwise. the mixture is stirred at room temperature for 30 minutes, a further 114 mg of sodium borohydride are added and finally the mixture is stirred at room temperature for a further 30 minutes. Thereafter, the aqueous phase is washed with methylene chloride and then adjusted to pH 6-7 with IN hydrochloric acid, whereby crystallization occurs. The separated crystals are filtered off. washed with water and ether and finally dried in a high vacuum, whereby there are obtained 0.6 g (27%) of N-benzyl-3-carbamoyl-D-alanine as a white powder. MS: 223 (M+H)+ Example 54 80 mg (0.13 mmol) of ethyl (R)-3-[[(S)—1—[[(1S.2S.4S)-25 -1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]- carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-4-phenylbutyrate are taken up in 2 ml of a 5.6 molar alcoholic dimethyl-amine solution and heated to reflux for 3 hours. The solution is then evaporated and the residue is chromato-30 graphed on silica gel with a 20:1 mixture of methylene chloride and methanol, whereby there are obtained 33 mg (20%) of (S)-N-[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy--4-isopropyl-5-hexenyl]-a-[(R)-a-[(dimethylcarbamoyl)-methyl]hydrocinnamamido]imidazole-4-propionamide as an 35 amorphous powder. MS: 608 (M+H)+ 22 6 3 9 5 10 15 - 118 -Example 55 The following compounds were manufactured in an analogous manner to that described in Example 40: From 117 mg (0.3 mmol) of (S)-a-amino-N--[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexeny1]imidazole-4-propionamide and 75 mg (0.3 mmol) of N-benzyl-3-ethoxycarbonyl-D--alanine 85 mg (45%) of ethyl (R)-3-(benzyl-amino)-3-[[(S)-l-[[(IS.2S.4S)-1(eyelohexylmethyl)--2-hydroxy-4-isopropy1-5-hexyl]carbamoy1]-2--imidazol-4-ylethyl]carbamoyl]propionate as an amorphous powder. MS: 624 (M+H)*; from 117 mg (0.3 mmol) of (S)-a-amino-N--[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-imidazole-4-propionamide and 88 mg (0.3 mmol) of N-benzyloxycarbonyl-L--asparagine 136 mg (71%) of benzyl [(S)-l-[[(S)--l-[[(IS.2S.4S)-l-(eyelohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethy1]carbamoyl]-2-carbamoylethyl] carbamate as an amorphous powder. MS: 639 (M+H)*; - from 157 mg (0.4 mmol) of (S)-a-amino-N- -[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 136 mg (0.4 mmol) of N-benzoyl-Y-benzyl-D--glutamate 115 mg (40%) of benzyl (S)-4--benzamido-4-[[(3)—1—[[(IS.2S.4S)-l-(cyclohexylmethyl) -2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl] -2-imidazol-4-ylethyl]carbamoyl]butyrate. MS: 714 + 20 30 35 (M+H) from 100 mg of (S)-a-amino-N-[(1S.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide and 64 mg of (RS)-a-[[(2-hydroxyethyl)carbamoyl]methyl]- ** 639$ 10 15 - 119 - hydrocinnamic acid 50 mg of (S)-N-[(IS,2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-[(RS)-a-[[(2-(hydroxethyl)-carbamoyl]methyl]hydrocinnamido]imidazole-4--propionamide as a 1:1 epimer mixture, MS: 624 (M+H) + : from 100 mg of (S)-a-amino-N-[(IS,2S,4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide and 80 mg of a-[(phenethylcarbamoyl)methyl]cinnamic acid 65 mg (37%) of (S)-N-[(IS,2S,4S)-1-(eyelohexy1-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]-a-[a--[(phenethylcarbamoyl)methy1]cinnamamido]imidazole -4-propionamide, MS: 682 (M+H)+; from 214 mg (0.55 mmol) of (S)-a-amino-N--[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 160 mg (0.55 mmol) of (RS)-a-[2-(morpholino-carbonyl)ethyl]hydrocinnamic acid 210 mg (60%) of (S)-N-[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4 -isopropy1-5-hexenyl]-a-[(RS)-a-[2-(morpholinocar bonyl)ethyl]hydrocinnamyl]imidazole-4-propion- 25 + amide as a 1:1 epimer mixture, MS: 664 (M+H) ; from 100 mg (0.25 mmol) of (S)-a-amino-N- -[(IS,2S,4S)-1(cyclohexylmethyl)-2-hydroxy-4- -isopropy1-5-hexenyl]imidazole-4-propionamide and 100 mg (0.28 mmol) of N-[(4-biphenylmethyl)- carbamoylJ-3-phenyl-L-alanine 150 mg (77%) of l-(4-biphenylmethyl)-3-[(S)-l[[(S)-l-[[(1S.2S.4S)- -l-(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5- -hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]- 20 30 35 carbamoyl]phenethyl]urea, MS: 748 (M+H)+ The respective acids used as the starting materials were prepared as follows: ^2 6 39 5 10 15 20 - 120 - N-Benzyl-3-ethoxvcarbonyl-D-alanine 574 mg (2.9 mmol) of fl-ethyl-D-aspartic acid, which was prepared according Co the method described by Pivitti in Gazetta. 18.. 480 (1888) for the preparation of the racemic compound, are dissolved in 2.9 ml of 2N sodium hydroxide solution and treated with 0.3 ml of benzaldehyde and subsequently stirred vigorously at room temperature for one hour. 33 mg of sodium borohydride are then added and the mixture is stirred at room temperature for a further hour. Thereafter, a further 33 mg of sodium borohydride are added and the mixture is stirred at room temperature for a further hour. The mixture is subsequently extracted with ether and thereafter the aqueous phase is adjusted to pH 6-7. whereby crystallization occurs. The separated crystals are filtered off and dried in a high vacuum, whereby there are obtained 81 mg (10%) of N-benzyl-3-ethoxycarbonyl-D--alanine which is used directly in the next step. MS: 206 (M-COOH)+ N-Benzoy1-Y-benzy1-D-qlutamate y-Benzyl-D-glutamate is benzoylated according to the 2 5 method described by Miller and Waelsch in Arch. Biochem. Biophys. 1952. 35.. 176 for the benzoylation of y ethyl--L-glutamate. whereby the desired product is obtained in 75% yield. MS: 341 (M)+ 30 (RS)-a-T T(2-(Hydroxyethvl)carbamoy11methy11hydro cinnamic acid 150 mg (0.8 mmol) of benzalsuccinic acid anhydride [S.G. Cohn et al.. JACS. 90. 3495 (1968)] in 10 ml of methylene chloride are treated with 0.048 ml of ethanol-35 amine and stirred at room temperature for 2 hours. The separated crystals are filtered off and dried, whereby there are obtained 155 mg (78%) of a-[[(2-(hydroxethyl)~ carbamoyl]methyl]cinnamic acid as colourless crystals. MS: 249 (M)+ **6 39 5 - 121 - 10 15 20 180 mg of the above-named acid in 5 ml of ethanol ate hydrogenated at room temperature for 2 hours in the presence of 2 ml of palladium-on-carbon. Thereafter, the catalyst is filtered off and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with 0.1N hydrochloric acid. The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure, whereby there are obtained 125 mg (70%) of (RS)-g-[[(2-hydroxy-ethyl)carbamoyl]methyl]hydrocinnamic acid which is used directly in the next step. g-f(Phenethylcarbamoyl)methvllcinnamic acid 226 mg (1.2 mmol) of benzalsuccinic acid anhydride are treated in 20 ml of methylene chloride with 0.15 ml of 2-phenethylamine and subsequently stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is chromatographed on silica gel, whereby there are obtained 260 mg (70%) of g-[(phenethylcarbamoyl)methyl]cinnamic acid, MS: 309 (M) + 25 (RS)-g-T 2-(Morpholinocarbonyl)ethyl1hydrocinnamic acid 2.5 g (10 mmol) of benzylmalonic acid diethyl ester and 1.45 ml (10 mmol) of t-butyl acrylate in 5 ml of acetonitrile are treated with 1.49 ml of DBU and stirred 30 at room temperature for 6 hours. Thereafter, the mixture is poured into dilute hydrochloric acid (pH 2), extracted with ether, the organic phase is washed with a small amount of water, dried over sodium sulphate and the solvent is removed under reduced pressure. In this manner 35 there are obtained 3.7 g (97%) of 4-t-butyl 2.2-diethyl l-phenyl-2.2,4-butanetricarboxylate as a pale yellow oil which is used directly in the next step. 22 6 3 9 5 10 20 25 30 35 - 122 - 1.9 g (5.4 mmol) of 4-t-butyl 2,2-diethyl 1-phenyl--2.2.4-butanetricarboxylate in 20 ml of ethanol are treated with 27 ml of 2N sodium hydroxide solution (54 mmol) and subsequently stirred at 50° for 6 hours. Thereafter, the reaction mixture is extracted with ether, the extracts are dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is chromatographed using a 10:1 mixture of methylene chloride and methanol as the eluting agent, whereby there is obtained 0.8 g (50%) of 3-ethyl 2.4-dihydrogen l-phenyl-2.2.4-butanetricarboxylate as an oil. MS: 250 + 15 (M~c°2) 800 mg of 3-ethyl 2.4-dihydrogen l-phenyl-2.2.4--butanetricarboxylate are heated to 170° for 2 hours in a high vacuum and subsequently chromatographed on silica gel by means of a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 600 mg (88%) of (RS)-4-(ethoxycarbonyl)-5-phenylvaleric acid as an oil which is used directly in the next step, MS: 250 (M+) 600 mg (2.4 mmol) of (RS)-4-(ethoxycarbonyl)-5-phenyl-valeric acid in 20 ml of acetonitrile are treated with 1.06 g (2.4 mmol) of BOP. 310 mg of Hiinig base and 0.21 ml of morpholine and stirred firstly at room temperature for 1 hour and thereafter at 50° for 2 hours. After usual working-up and chromatography on silica gel using a 10:1 mixture of methanol and chloroform as the eluting agent there are obtained 400 mg (52%) of (RS)-a-[2--(morpholinocarbonyl)ethyl]hydrocinnamic acid ethyl ester which is used directly in the next step. MS: 319 (M+) 400 mg (1.25 mmol) of the above-named ester in 10 ml of ethanol are treated with 5 ml of 0.5N sodium hydroxide solution and subsequently stirred at 50° for 2 hours. After usual working-up and chromatography on silica gel 22 6 3 9 5 - 123 - using a 10:1 mixture of methylene chloride and methanol there are obtained 170 mg (47%) of (RS)-a-[2--(morpholinocarbonyl)ethyl]hydrocinnamic acid as an oil which is used directly in the next step. MS: 291 (M+) N-r(4-Biphenvlmethyl)carbamoyl1-3-phenvl-L-alanine 23 3.9 g (21.3 mmol) of biphenylmethylamine and 7.2 ml of Hiinig base in 200 ml of toluene are treated while cooling in a ice bath with 10.5 ml of phosgene in toluene (20%) and stirred at 0° for 1 hour. Thereafter. 9 g of L-phenylalanine benzyl ester 4-toluenesulphonate are added and the solution is stirred at 80° for 12 hours. Subsequently, the mixture is partitioned between methylene chloride and water, the organic phase is dried over sodium sulphate, the solvent is removed under reduced pressure and the product is isolated by chromatography on silica gel using a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 7.3 g (74%) of N-[(4--biphenylmethyl)carbamoyl]-3-phenyl-L-alanine benzyl ester. 3.2 g (6.7 mmol) of the above-named benzyl ester in 100 ml of ethanol are hydrogenated at room temperature in the presence of 320 mg of palladium-on-carbon until the theoretical amount of hydrogen has been taken up. Thereafter, the catalyst is filtered off, the filtrate is evaporated and the residue is crystallized from ethanol/ methylene chloride/ether, whereby there are obtained 2.1 g (65%) of N-[(4-biphenylmethyl)carbamoyl]-3-L-alanine in the form of white crystals, melting point 169-170°. Example 56 57 mg of N-[(IS,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy--4-isopropyl-5-hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide, 21 mg of t-butoxycarbonyl-L-azetidine-2- 23 A. Kamil et al., Czech. 163. 819 (1976) 226395 10 15 20 25 30 35 - 124 - -carboxylic acid, which was prepared from azetidine-carboxylic acid by t-butoxycarbonylation according to the method described by O. Keller et al. in Org. Synth. 631, 160. 1985. 47 mg of BOP and 0.021 ml of Htinig base in 5 ml of acetonitrile are stirred at room temperature for 8 hours and thereafter worked-up in the usual manner. The crude product is purified by chromatography on silica gel with a 10:1 mixture of methanol and chloroform, whereby there are obtained 69 mg of t-butyl [(S)-2-[(S)-a-[<S)--l-[[(lS.2S,4S)-l-(cyclohexylmethyl) -2-hydroxy-4--isopropyl-5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoy1]phenethy1]carbamoyl]-l-azetidinecarboxylate in the form of white crystals. MS: 721 (M+H)+. Example 57 56 mg of t-butyl [(S)-2-[(S)-a-[(S)-l-[[(1S.2S.4S)--1-(cyclohexylmethy1)-2-hydroxy-4-isopropy1-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]phenethyl]-carbamoyl]-l-azetidinecarboxylate in 5 ml of ethanol are hydrogenated at room temperature for 2 hours in the presence of 10 mg of palladium-on-carbon. Thereafter, the catalyst is filtered off and the solvent is evaporated under reduced pressure, whereby there are obtained 47 mg of t-butyl (S)-2-[[(S)-a-[[(S)-l-[[(1S.2S.4S)-1-(cyclohexylmethyl ) -2-hydroxy-4-isopropylhexyl]carbamoyl]-2--imidazo1-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-l--azetidinecarboxylate in the form of white crystals. MS: 723 (M+H)+ In an analogous manner, by hydrogenating 90 mg of (S)-N-[(IS,2S,4S)-l-(eyelohexylmethyl)-2-hydroxy-4-isopr opy 1-5- hexeny 1 ] -a- [(RS)-a-[(eyelopentylcarbonyl)-methyl]hydrocinnamamido]imidazole-4-propionamide there 22 6 3 9 5 10 15 20 25 30 35 - 125 - were obtained 78 mg of (S)-N-[(IS.2S.4S)-1-(cyclohexylmethyl) -2-hydr oxy- 4 -isopropylhexyl]-a-[(RS)-a--[(eyelopentylcarbonyl)methyl]hydrocinnamamido]imdiazole-4--propionamide in the form of an amorphous solid as a 1:1 epimer mixture. MS: 635 (M+H)+ Example 58 The following compounds were manufactured in an analogous manner to that described in Example 56: From 75 mg of N-[(lS.2S.4S)-l-(cyclohexylmethyl)- -2-hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L- -alanyl)imidazole-4-propionamide and 30 mg of (3R,8aR)-hexahydro-8a-methyl-5-oxo-5H-thiazolo- 24 [3.2-a]pyridine-3-carboxylic acid 64 mg (64%) of (S)-N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopro-pyl-5-hexenyl]-a-[(RS)-a--[(3R.8aR)-hexahydro-8a-methyl-5-oxo~5H-thiazolo--[3.2-a]pyridine-3-carboxamido]hydrocinnamamido]--imidazole-4-propionamide as a white solid, MS: 73 5 (M+H)+; from 75 mg of N-[(lS.2S.4S)-l-(cyclohexylmethyl)- -2-hydroxy-4-isopropy1-5-hexeny1]-a-(3-phenyl-L- -alanyl)imidazole-4-propionamide and 30 mg of (3R,7aR)-tetrahydro-7a-methylpyrrolo[2.1-b]- 24 thiazole-3-carboxylic acid 86 mg of (3R.7aR)--N-[(S)-a-[[(S)-l-[[(IS.2S.4S)-1-(cyclohexylmethyl ) -2-hydr oxy- 4- isopr opyl- 5-hexenyl] car bamoy 1 ] -2-imidazol-4-ylethyl]carbamoyl]phenethyl]hexa-hydro-5-oxo-pyrrolo[2.1-b]thiazole-3-carboxamide as an amorphous solid. MS: 721 (M+H)+; from 75 mg of N-[(lS.2S.4S)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 34 mg of N-t-butoxycarbonyl-L-methionine 90 mg of t-.butyl 24 J.E. Baldwin et al.. JACS 100. 4597 22 6 3 9 5 - 126 - [ (S)-l-[[(S)-<x-[ [ (S)-l-C r (is. 2S.4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-phenethy1]carbamoy1]-2-(methylthio)ethyl] carbamate as an amorphous solid, MS: 769 (M+H)+; from 75 mg of N-[(IS,2S,4S)-1-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and 32 mg of N-isovaleryl-L-methionine, which in turn was prepared by reacting L-methionine methyl ester with isovaleric acid chloride and subsequently saponifying of the methyl ester. 61 mg of (S)-N-[(IS,2S,4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]-a-[(S)-a-[(S)-4-(methyl-thio)-2-isovaleramidobutyramido]hydrocinnamamido]--imidazole-4-propionamide as an amorphous solid, MS: 753 (M+H)+; Example 59 A mixture of 95 mg of (RS)-a-[(2-morpholinoethyl)-carbamoylmethyl]-l-naphthalenepropionic acid, 100 mg of (S)-a-amino-N-[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy--4-isopropyl-5-hexenyl]imidazole-4-propionamide and 97 mg of HBTU in acetonitrile is stirred at room temperature for 3.5 hours and then worked-up in the usual manner. The residue is chromatographed on silica gel with a 4:1 mixture of methylene chloride and methanol as the eluting agent, whereby there are obtained 60 mg of N-[(IS.2S.4S)--1-(eyelohexylmethyl)-2-hydroxy-4 -isopropy1-5-hexenyl]--a-[3-[(2-morpholinoethyl)carbamoyl]-2-(1-naphthylmethyl)-propionamido]imidazole-4-propionamide as a foam. MS: 743 (M+H)+ 22 6 3 9 5 10 15 20 30 - 127 - The (RS)-a-[(2-morpholinoethyl)carbamoylmethyl]-l--naphthalenepropionic acid used as the starting material was prepared as follows: 0.72 g of DCC is added to 1.0 g (3.5 mmol) of (RS)-3- 25 -(ethoxycarbonyl)-4-(l-naphthyl)butyric acid in 50 ml of methylene chloride and the suspension obtained is stirred at room temperature for 2 hours. Subsequently, 0.46 ml (3.5 mmol) of 4-(2-aminoethyl)morpholine is added and the mixture is stirred at room temperature for a further 18 hours. After usual working-up the residue is flash chromatographed on silica gel with a 20:1 mixture of methylene chloride and methanol as the eluting agent, whereby there is obtained 0.5 g of (RS)-a-[(2--morpholinoethyl)carbamoylmethyl]-l -naphthalenepropionic acid ethyl ester in the form of a pale yellow resin. MS: 398 (M)+ 0.5 g (1.25 mmol) of the above-named ethyl ester in ethanol is treated with 2.5 ml of IN sodium hydroxide solution and stirred at 80° for 6 hours. Thereafter, the reaction mixture is adjusted to pH 6 and the solvent is removed under reduced pressure. The residue is suspended 25 in a 1:1 mixture of methylene chloride and methanol, the insoluble salts are filtered off. the filtrate is dried over sodium sulphate and the solvent is evaporated under reduced pressure. In this manner there are obtained 500 mg of (RS)-a-[(2-morpho1inoethyl)carbamoylmethyl]-l--naphthalenepropionic acid in the form of a yellow foam which is used directly in the next step. Example 60 35 A mixture of 153 mg (0.4 mmol) of (S)-a-amino-N- -[(IS.2S.4S)-l-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide. 98 mg of (R)-a-(pivaloyl- 25 EPA 0.181.110 22 6 3 9 5 - 128 - 10 methyl)hydrocinnamic acid. 175 mg of BOP and 0.14 ml of Hiinig base in 10 ml of acetonitrile is stirred at room temperature for 12 hours and thereafter worked-up in the usual manner. Chromatography of the residue on silica gel using a 10:1 mixture of methylene chloride and methanol as the eluting agent yields 120 mg of N-[(lS,2S,4S)-l-benzyl--2-hydroxy-4-isopropyl -5-hexenyl]-a-(a-pivaloyl-hydrocinnamamido)imidazole-4-propionamide as white crystals. MS: 615 (M+H)+. The (S)-a-amino-N-[(IS.2S.4S)-1-benzy1-2-hydroxy-4- -isopropyl-5-hexenyl]imidazole-4-propionamide used as the starting material was prepared as follows: In an analogous manner to that described in Example 1 for the preparation of (aS.BS)-fl-t-butoxycarbonylamino- -a-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol. from 56.6 g (320 mmol) of (RS)-2-isopropyl-3-butenyl bromide 7.7 g of magnesium and 24.2 g of N-t-butoxycarbonyl-L-26 -phenylalanal there were obtained 15.6 g (49%) of t-butyl [(lS.2S.4S)-l-benzyl-2-hydroxy-4-isopropyl-5--hexenyl] carbamate as an epimer mixture. The desired (IS.2S.4S)-epimer was isolated as the less polar isomer, 25 MS: 256 (M-benzyl)+. by flash chromatography on silica gel using a 9:1 mixture of methylene chloride and ether ?s the eluting agent. 15 20 30 2.2 g of t-butyl [(lS.2S.4S)-l-benzyl-2-hydroxy-4--isopropyl-5-hexenyl] carbamate are stirred at room temperature for 2 hours in 70 ml of 1.8N hydrogen chloride in dioxan. Thereafter, the reaction mixture is poured into sodium bicarbonate solution and extracted with ether at pH 3. Drying and evaporation of the ether extracts and 35 chromatography of the residue on silica gel with a 5:1 mixture of methylene chloride and methanol yields 900 mg (60%) of (2S.3S,5S)-2-amino-5-isopropyl-l-phenyl-6-hepten--3-ol as an oil, MS: 248 (M)+. 26 Evans et al., J. Org. Chem.. 50, 4615 (1985) 22 6 3 9 5 10 15 20 30 - 129 - A mixture of 1.22 g (2.83 mmol) of N-a-N-im-di-t--butoxycarbonyl-L-histidine, 700 mg (2.83 mmol) of (2S,3S.5S)-2-amino-5-isopropy1-1-phenyl-6-hepten-3-ol, 1.25 g of BOP and 0.58 ml of Hiinig base in 20 ml of acetonitrile is stirred at room temperature for 12 hours and thereafter worked-up in the usual manner. Chromatography of the residue on silica gel using a 2:1 mixture of methylene chloride and ether yields 1.0 g (10%) of t-butyl 4-[(S)-2-[[(IS.2S.4S)-l-benzy1-2-hydroxy-4-isopropy1-5--hexenyl]carbamoyl]-2-(1-t-butoxyformamido)ethyl]imidazole--1-carboxylate in the form of a foam, MS: 585 (M+H)+. 1 g (1.7 mmol) of t-butyl 4-[(S)-2-[[(1S.2S.4S)-1--benzy1-2-hydroxy-4-isopropyl-5-hexeny1]carbamoyl]-2-(1-t--butoxyformamido)ethyl]imidazole-l-carboxylate are dissolved in 7 ml of 5N hydrogen chloride in dioxan and subsequently stirred at room temperature for 2 hours. Thereafter, the reaction mixture is poured into sodium carbonate solution and extracted with ethyl acetate. The organic extract is dried and evaporated and the residue is chromatographed on silica gel with a 3:1 mixture of methylene chloride and methanol, whereby there are 25 obtained 340 mg (52%) of (S)-a-amino-N-[(1S.2S.4S)-1- -benzy1-2-hydroxy-4-isopropy1-5-hexenyl]imidazole-4-propionamide as a foam, MS: 385 (M+H)+. Example 61 120 mg of N-[(IS,2S.4S)-l-benzyl-2-hydroxy-4--isopropy1-5-hexenyl]-a-(a-pivaloylhydrocinnamamido)-imidazole-4-propionamide in 10 ml of ethanol are hydrogenated at room temperature for 2 hours in the 35 presence of 20 mg of palladium-on-carbon. Thereafter, the catalyst is filtered off and the solvent is evaporated under reduced pressure, whereby (S)-N-[(1S.2S.4S)-1--benzy1-2-hydroxy-4-isopropylhexyl]-a-[(R)-a-(3.3- 22 6 3 9 5 - 130 - -dimethy1-2-oxobutyl)hydrocinnamamido]imidazole-4-propion-amide is obtained as a foam. MS: 617 (M+H)+ Example 62 A mixture of 256 mg (1.03 mmol) of (2S.3S.5S)-2--amino-5-isopropyl-l-phenyl-6-hepten-3-ol, 414 mg of Boc-Phe-His-OH, 0.354 ml of Hiinig base and 455 mg of BOP in 20 ml of acetonitrile is stirred at room temperature for 12 hours and then worked-up in the usual manner. By flash chromatography of the residue on silica gel using a 7:1 mixture of methylene chloride and methanol there are obtained 385 mg (61%) of t-butyl [(S)-a-[[(RS)-l--[[(IS.2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]-carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]phenethyl] carbamate as a 4:1 epimer mixture. MS: 632 (M+H)+ Example 63 334 mg (0.53 mmol) of t-butyl [(S)-a-[[(RS)-l--[[(IS.2S.4S)-1-benzy1-2-hydroxy-4-isopropy1-5-hexenyl]-carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl] carbamate are dissolved in 3 ml of 5.2N hydrogen chloride in dioxan and the mixture is stirred at room temperature for 2 hours. After the usual working-up 100 mg of the crude product obtained are dissolved in 10 ml of acetonitrile, 40.4 mg (0.188 mmol) of t-butoxycarbonyl-D--proline. 0.064 ml of Hiinig base and 83 mg of BOP are added and the reaction mixture is subsequently stirred at room temperature for 12 hours. After usual working-up the residue is chromatographed on silica gel using a 10:1 mixture of methylene chloride and methanol, whereby there are obtained 78 mg (56%) of t-butyl (R)-2-[[(S)-a-[(RS)--l-[[[(IS,2S,4S)-l-benzyl-2 -hydroxy-4-isopropyl-5- 22 6 3 9 5 15 - 131 - -hexeny1]carbamoyl]-2-imidazo1-4-ylethyl]carbamoyl]-phenethyl]carbamoyl]-l-pyrolidinecarboxylate in the form of white crystals as a 4:1 epimer mixture. MS: 729 (M+H)+ Example 64 10 0.65 g of (S)-a-amino-N-[(IS.2S.4RS)-2-hydroxy-l--isobutyl-4-isopropyl-5-hexenyl] imidazole-4-propionamide in 20 ml of acetonitrile are added together with 0.36 ml of ethyldiisopropylamine to a solution of 0.45 g of 2-benzyl-3-phenylpropionic acid (which was prepared according to the method described in J. Am. Chem. Soc. 71. 1863 (1949)) and 0.8 g of BOP in 30 ml of acetonitrile and the mixture is stirred at room temperature for 20 hours. Subsequently, the reaction mixture is evaporated under reduced pressure, the residue is dissolved in 50 ml of ethyl acetate and the organic solution is washed twice with 100 ml of water each time, dried over sodium sulphate and evaporated. The residue is separated by flash chromatography on 100 g of silica gel with a 250:15 mixture of methylene chloride and methanol as the eluting 25 agent, whereby there is obtained 0.17 g of (S)-a-(2,2- -dibenzylacetamido)-N-[(lS.2S.4S)-2 -hydroxy-l-isobutyl-4--isopropyl-5-hexenyl]imidazole-4-propionamide as a white powder, melting point 120°. This compound corresponds to the less polar isomer and has a Rf value of 0.14. 30 The (S)-a-amino-N-[(IS.2S,4RS)-2-hydroxy-l-isobutyl--4-isopropyl-5-hexenyl]imidazole-4-propionamide used as the starting material was prepared as follows: 0.72 g of (4S)-amino-(5S)-hydroxy-7-isopropyl-2-35 -methyl-8-nonene in 20 ml of dimethylformamide are added together with 0.7 ml of ethyldiisopropylamine to a solution of 2 g of N-a-N-im-bis-Fmoc-L-histidine and 1.47 g of BOP in 20 ml of dimethylformamide and the 20 22 6 3 9 5 10 15 20 25 30 35 - 132. - mixture is stirred at room temperature for 20 hours. Subsequently, the reaction mixture is evaporated under reduced pressure, the residue is dissolved in 60 ml of ethyl acetate and the organic phase is washed twice with 200 ml of water each time, dried over sodium sulphate and evaporated. The crude product is purified by flash chromatography on 100 g of silica gel with a 250:20 mixture of methylene chloride and methanol as the eluting agent, whereby there are obtained 1.25 g of fluoren-9--ylmethyl [(S)-l-[[(IS.2S.4RS)-2-hydroxy-1-isobuty1-4--isopropyl -5-hexenyl]carbamoyl]-2-imidazo1-4-ylethyl] carbamate as a white powder. MS: 573 (M+H)+. 1.25 g of fluoren-9-ylmethyl [(S)-l-[[(lS.2S.4RS)-2--hydroxy-1-isobuty1-4-isopropyl -5-hexenyl]carbamoyl]-2--imidazol-4-ylethyl] carbamate are dissolved in 20 ml of piperidine and stirred at room temperature for 3 hours. Thereafter, the reaction mixture is poured on to 20 ml of ice/water and filtered. Evaporation of the filtrate yields 0.65 g of (S)-a-amino-N-[(IS.2S.4RS)-2-hydroxy-1--isobutyl -4-isopropy1-5-hexenyl]imidazole-4-propionamide as a white powder. MS: 269 (M-C4H5N2)+. Example 65 0.3 g of (S)-2-[[N-(t-butoxycarbonyl)-3-phenyl-L--alanyl]oxy]succinamidic acid are dissolved together with 0.35 g of BOP in 20 ml of acetonitrile with the addition of 2 ml of dimethylformamide, treated with a solution of 0.17 g of (4S)-amino-(5S)-hydroxy-7-isopropyl-2-methyl-8--nonene and 0.15 ml of ethyldiisopropylamine in 20 ml of acetonitrile and stirred at room temperature for 20 hours. Subsequently, the reaction mixture is evaporated under reduced pressure and the residue is dissolved in 50 ml of methylene chloride. The organic solution is washed in succession with 50 ml of 3N hydrochloric acid. 50 ml of 10 15 20 25 30 35 226395 - 133 - saturated sodium bicarbonate solution and 50 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by flash chromatography on 50 g of silica gel using a 10:1 mixture of methylene chloride and methanol as the eluting agent and subsequently crystallized from ether/methylene chloride. In this manner there is obtained 0.3 g of t-butyl [(S)-a-[[(S)-2-carbamoyl-l-[[(lS.2S.4RS)-2--hydroxy -1-isobuty1-4-isopropy1-5-hexenyl]carbamoyl]-ethoxy]carbonyl]phenethyl] carbamate as a white powder, melting point 75°. The (4S)-amino-(5S)-hydroxy-7-isopropy1-2-methy1-8--nonene used as the starting material was prepared as follows: 0.8 g of t-butoxycarbonyl-L-phenylalanine is dissolved in 5 ml of pyridine, treated at -5° with 0.3 ml of oxalyl chloride and stirred at 0-5° for 10 minutes. After the addition of 0.7 g of benzyl-(S)-3-carbamoyl-2--hydroxypropionic acid (which was prepared according to the directions in Agr. Biol. Chem. 40. 1651 (1976) and Int. J. Peptide Protein Res. 20. 35 (1982)) in 1 ml of pyridine the mixture is stirred firstly at 0-5° for 2 hours and thereafter at room temperature for 1 hour. The reaction mixture is then poured on to ice and extracted twice with 50 ml of ethyl acetate each time. The combined organic extracts are washed with 50 ml of 3N hydrochloric acid and 50 ml of saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue is purified by flash chromatography on 50 g of silica gel using a 10:1 mixture of methylene chloride and methanol as the eluting agent, whereby there is obtained 0.9 g of (S)-2-[[N-(t-butoxycarbonyl)-3-phenyl-L-alanyl]oxy]-succinamide benzyl ester as a yellow powder. MS: 397 (m-c4h9o)+. 22 6 3 9 5 - 134 - 0.9 g of the above benzyl ester is dissolved in 40 ml of ethanol and hydrogenated at normal pressure in the presence of 0.1 g of palladium-on-carbon (10%). After completion of the hydrogen uptake the catalyst is filtered off and the filtrate is evaporated. Crystallization of the residue from methylene chloride yields 0.52 g of (S)-2--[[N-(t-butoxycarbonyl)-3-phenyl-L-alany1]oxy]succinamidic acid as a white powder. MS: 381 (M+H)+. Example 66 A solution of 200 mg of (2S.3S.5S)-2-[Boc-His(3-Bom)--Pro-His-NH]-l-cyclohexy1-5-isopropy1-6-hepten-3-ol is hydrogenated exhaustively at room temperature in a 4:1 mixture of glacial acetic acid and water in the presence of 20 mg of palladium-on-carbon (10%). After completion of the hydrogen uptake (4 hours) the catalyst is filtered off and the filtrate is evaporated to dryness. The crystals obtained after chromatographic purification on silica gel are recrystallized from ethyl acetate/hexane, whereby there is obtained (2S.3S.5S)-2-(Boc-His-Pro-His-NH)-l--cyclohexyl-5-isopropyl-3-heptanol in 69% yield, melting point 135-136°. The preparation of the (2S.3S.5S)-2-[Boc-His(3-Bom)--Pro-His-NH]-1-cyclohexy1-5-isopropyl-6-hepten-3-ol used as the starting material is described in Example 68. Example 67 A solution of 100 mg of (S)-a-[[N-(t-butoxy-carbonyl)-B-phenyl-L-alanyl]oxy]imidazole-4-propionic acid. 78 mg of (aS.BS)-B-amino-a-[(S)-2-isopropyl-3--butenyl]cyclohexanepropanol and 55 mg of N-methyl-morpholine in 3 ml of dimethylformamide is treated with 102 mg of HBTU while stirring and gassing with argon. 22 6 3 9 5 10 15 20 25 30 - 135 - After leaving to stand overnight the reaction solution is poured into 5 ml of concentrated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts are dried and evaporated under reduced pressure and the crude product obtained in purified by chromatography on silica gel with a 95:5 mixture of methylene chloride and methanol as the eluting agent, whereby t-butyl [(S)-a-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl) -2-hydroxy-4-isopropy1-5-hexenyl]carbamoyl]--2-imidazole-4-ylethoxy]carbonyl]phenethyl] carbamate is obtained in 22% yield, melting point 72-75° (dec.). The (S)-a-[[N-(t-butoxycarbonyl)-fl-phenyl-L-alanyl]-oxy]imidazole-4-propionic acid used as the starting material was prepared as follows: 1.99 g of N-t-butoxycarbonyl-L-phenylalanine and 1.58 g of benzyl (S)-a-hydroxyimidazolepropionate are suspended in 25 ml of methylene chloride and stirred. After stirring at room temperature for 15 minutes 305 mg of 4-dimethylaminopyridine are added and the reaction mixture is cooled to -15°. After the dropwise addition of 2 ml of N-methylmorpholine and a solution of 6.6 g of propanephosphoric acid anhydride in 5 ml of methylene chloride the reaction mixture is stirred at -15° for a further 2 hours and thereafter left to stand at -18° for 6 days. After the addition of a few drops of water the reaction mixture is evaporated under reduced pressure and the oily residue is triturated for 2 hours with 100 ml of ethyl acetate and 25 ml of water. The organic phase is then washed in succession with aqueous sodium bicarbonate solution (5%) water and 1.5M citric acid. The colourless oil obtained after evaporation of the solvent under 35 reduced pressure is chromatographed on silica gel with a 95:5 mixture of methylene chloride and methanol as the eluting agent, whereby (S)-a-[[N-(t-butoxycarbonyl)-3- 226395 - 136 - -phenyl-L-alanyl]oxy]imidazole-4-propionic acid benzyl estec is obtained as a yellow oil in 13% yield. MS: 494 (M+H)+. A solution of 960 mg of the above-described benzyl ester in 20 ml of absolute ethanol is hydrogenated in the presence of 500 mg of palladium-on-carbon (10%) until the theoretical amount of hydrogen has been taken up. Thereafter, the catalyst is filtered off and the filtrate is evaporated under reduced pressure, whereby there is obtained an oily residue which crystallizes after the addition of methanol/ethyl acetate. In this manner there is obtained (S)-a-[[N-(t-butoxycarbonyl)-fl-phenyl-L--alanyl]oxy]imidazole-4-propionic acid in 18% yield, melting point 130-131°. Example 68 The following compounds were manufactured in an analogous manner to that described in Example 67: From (S)-a-amino-N-C(IS,2S.4S)-l(cyclohexyl-methyl )-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and N-(t-butoxycarbonyl)-3-(1--naphthyl)-L-alanine in 50% yield t-butyl [(S)—1— -[[(S)-l-[[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropy1-5-hexenyl]carbamoyl]-2--imidazo1-4-ylethyl]carbamoyl]-2-(1-naphthyl)-ethyl] carbamate, melting point 141-143° (from ethyl acetate/hexane); from (S)-a-amino-N-[(lS.2S.4S)-l(cyclohexyl-methy1)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and N-(t-butoxycarbonyl)-4--chlorophenylalanine in 41% yield t-butyl [(S)-l--[[(S)—1—[C(IS.2S.4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropy1-5-hexenyl]carbamoyl]-2- 22 6 3 9 5 - 137 - -imidazo1-4-ylethyl]carbamoyl]-2-(4-chloropheny)-ethyl] carbamate, melting point 220-221° (from ethanol/ethyl acetate); from (S)-a-amino-N-f(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and N-t-butoxycarbonyl-L-phenyl-glycine in 39% yield t-butyl [(S)-a-[[(S)-l--[[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4-yl--ethyl]carbamoyl]benzyl] carbamate, melting point 125-126° (from ethyl acetate/hexane); from (S)-a-amino-N-f(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and N-t-butoxycarbonyl-L-cyclo-hexylglycine in 54% yield t-butyl [(S)-a-[[(S)--l-[[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]eyelohexylmethyl] carbamate, melting point 139-140° (from ethyl acetate/ hexane); from (S)-a-amino-N-[(lS.2S,4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and t-butoxycarbonyl-D-phenyl-alanine in 48% yield t-butyl [(R)-a-[[(S)-l--[[(lS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]phenethyl] carbamate, melting point 195° (from ethyl acetate); from (S)-a-amino-N-[(lS.2S.4S)-l-(cyclohexyl-methyl)-2-hydroxy-4-isopropy1-5-hexenyl]imidazole--4-propionamide and t-butoxycarbonyl-L-cyclo-hexylalanine in 22% yield t-butyl [(S)-2-cyclo-hexyl-l-[[(S)-l-[[(lS.2S.4S)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropyl-5-hexeny1]carbamoyl]-(2--imidazo1-4-ylethyl]carbamoyl]ethyl] carbamate, melting point 116° (from ethyl acetate/ diisopropyl ether); 22 6 3 9 5 - 138 - from N-[(IS.2S.4S)-l-(eyelohexylmethyl)-2--hydroxy-4-isopropy1-5-hexenyl]-a-(3-phenyl-L--alanyl)imidazole-4-propionamide and N-[5-(l-t--butoxyformamido)valeryl]-fl-alanine in 40% yield t-butyl [4-[[-2-[[(S)-a-[[(S)-l-[[(lS.2S.4S)-l--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]carbamoyl]-2-imidazo1-4-ylethyl]-carbamoyl]phenethyl]carbamoyl]ethyl]carbamoyl]-butyl] carbamate, melting point 114-115° (from ethyl acetate): from (S)-a-amino-N-t(lS.2S,4S)-l-(cyclohexyl-methy1)-2-hydroxy-4-isopropyl-5-hexeny1]imidazole--4-propionamide and Boc-His(3-Bom)-Pro-OH in 51% yield (2S.3S.5S)-2-[Boc-His(3-Bom)-Pro-His-NH]-l--cyclohexy1-5-isopropy1-6-hepten-3-o1. melting point 121-122° (from ethyl acetate/hexane). The acids used as the starting materials are either known and commercially available or were prepared as follows: N-T 5-(1-t-Butoxyformamido)valery11-fl-alanine To a suspension of 7.68 g of fl-alanine ethyl ester hydrochloride in 50 ml of methylene chloride are added while stirring in the given sequence 5.56 g of triethyl-araine. 10.86 g of N-t-butoxycarbonyl-5-aminovaleric acid, dissolved in 50 ml of methylene chloride, and portionwise 11.35 g of DCC. After completion of the addition the reaction mixture is stirred at room temperature overnight and thereafter filtered off from separated urea. The filtrate is washed in succession with 250 ml of sodium bicarbonate solution (5%). water. 250 ml of 0.1M citric acid and finally with saturated sodium chloride solution. Thereafter, the solvent is evaporated under reduced pressure and the oily residue is purified by column chromatography on silica gel. whereby N-[5-(l-t--butoxyformamido)valeryl]-fl-alanine ethyl ester is obtained in 59% yield, melting point 28° (from hexane). 11 6 3 9 5 - 139 - 3.94 g of the above-named ester are dissolved in 20 ml of methanol and there are added while stirring at 0° firstly l mol equivalent and after 30 minutes a further 5 0.2 mol equivalents of IN sodium hydroxide solution. The mixture is then stirred at room temperature for one hour, 1.2 mol equivalents of IN hydrochloric acid (pH 4) are added portionwise, the solvent is evaporated under reduced pressure and the aqueous phase is extracted several times 10 with methylene chloride. Drying and evaporation of the extracts yields an oily residue which crystallizes by the addition of hexane. Recrystallization from hexane yields N-[5-(l-t-butoxyformamido)valeryl]-J3-alanine in 87% yield, melting point 70°. 15 Example 69 5 ml of a 4 molar solution of hydrogen chloride in dioxan are added to 1.06 g (3 mmol) of t-butyl 2o t(IS,2S,4S)-4-(2-furyl)-2-hydroxy-l-isobutyl-5-methylhexyl] carbamate in 8 ml of acetic acid. After 30 minutes the solvent is evaporated under reduced pressure, the residue is digested with toluene and the solvent is again evaporated. The thus-obtained residue is dissolved in 25 10 ml of absolute dimethylformamide and there are added to the solution 1.8 g (3 mmol) of N-a-N-im-bis-Fmoc-L--histidine in 10 ml of tetrahydrofuran, 0.35 ml of N-methylmorpholine and 0.8 g (5.6 mmol) of N-hydroxybenzo-triazole. This solution is cooled to -10° and treated 30 dropwise with 5 ml of a 1 molar DCC solution in tetrahydrofuran. The reaction mixture is stirred overnight and thereafter filtered. The solution is treated with 5 ml of a 50% piperidine-dimethylformamide solution and, after 30 minutes, evaporated in a high vacuum. The residue is dissolved in ethec and the organic phase is washed in succession with water, a sodium carbonate solution and 22 6 3 9 5 - 140 - again with water. Thereafter, the organic phase is dried over sodium sulphate and evaporated under reduced pressure. The residue is then dissolved in 10 ml of dimethylformamide and there are added 0.8 g (3 mmol) of N-t-butoxycarbonyl-phenylalanine in 10 ml of tetrahydrofuran. 0.35 ml of N-methylmorpholine. 0.8 g (5.6 mmol) of N-hydroxybenzotriazole and 5 ml of a 1 molar DCC solution in tetrahydrofuran. The reaction mixture is stirred overnight and thereafter filtered. The filtrate is evaporated in a high vacuum and the residue is dissolved in ether. The organic solution is washed with water, a sodium carbonate solution and once more with water, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed with a 19:3 mixture of methylene chloride and ethyl acetate as the eluting agent, whereby 0.65 g of (S.S.S)-l--(Boc-Phe-His-NH)-methylbutyl-Y-isopropy1-2-furane-propanol is obtained as a thick oil. MS: 638 (M+H)+. The t-butyl [(lS.2S.4S)-4-(2-furyl)-2-hydroxy-l--isobutyl-5-methylhexylJ carbamate used as the starting material was prepared as follows: 340 g (2.5 mmol) of zinc chloride are added in one portion to a solution of 217 g (1.67 mol) of 2.5-dimethoxy-2,5-dihydrofuran, 1500 ml (10 mol) of malonic acid diethyl ester, 167 ml of water and 330 ml of glacial acetic acid, whereby the temperature rises to 35°. The dark solution is stirred at room temperature overnight, thereafter poured on to ice. extracted three times with diethyl ether, washed in succession with saturated sodium bicarbonate and sodium chloride solutions and finally dried. After evaporating the excess malonic acid diethyl ester (70°/13 Pa) the remaining oil is distilled over a Vigreux column, whereby there are obtained 109.2 g (29%) of 2-furylmalonic acid diethyl ester (purity 94%). boiling point 100-110°/39 Pa. 226395 - 141 - 24 g (1 mol) of sodium hydride are suspended in 100 ml of absolute tetrahydrofuran. A solution of 218.4 g (0.97 mol) of 2-furylmalonic acid diethyl ester in 200 ml 5 of absolute tetrahydrofuran is added dropwise. whereby the temperature rises to 30° (blue suspension). After stirring at 30° for 30 minutes 340 g (200 ml; 2 mol) of isopropyl iodide are added dropwise within 30 minutes. The reaction mixture is heated to reflux overnight, thereafter 10 evaporated under reduced pressure and dissolved in ether. After evaporation of the solvent the remaining oily residue is distilled in a high vacuum, whereby there are obtained 240.6 g (92.5%) of 2-furyl-2-isopropylmalonic acid diethyl ester (purity 93.6%) in the form of a 15 yellowish oil. boiling point 85-88V13 Pa. 240.6 g (0.9 mol) of 2-furyl-2-isopropylmalonic acid diethyl ester are dissolved in 500 ml of dimethyl sulphoxide. treated with 2000 ml of 2N sodium hydroxide 2o solution and heated to reflux for 2 hours. After cooling the reaction mixture is poured into dilute sulphuric acid and extracted exhaustively with ether. The organic extracts are thereafter dried and the solvent is evaporated under reduced pressure. In this manner there 2^ are obtained 148.7 g (98%) of (±) 2-(2-furyl)-3-methyl-butyric acid in the form of a thick yellowish oil. 161.0 g (0.96 mol) of (±) 2-(2-furyl)-3-methyl- butyric acid are dissolved in 1000 ml of ether and treated 30 with 109 g (0.9 mol) of S(-)-a-phenylethylamine in 100 ml of ether. The separated crystals are filtered off and recrystallized three times from 600 ml of ethyl acetate. In this manner there are obtained 80 g of white 20 crystals, melting point 135-136°. [a]D = -14.1° (c __ = 2%. methanol). 22 6 39 - 142 - These crystals are suspended in ethyl acetate and acidified with a 3N hydrochloric acid solution while cooling with ice. The organic solution is washed with water, dried and evaporated under reduced pressure. whereby there are obtained 46.7 g of (+) 2-(2-furyl)-3- -methylbutyric acid as a viscous oil (purity 98.6%). 20 [a]p = +29.9° (c = 1%. ethyl acetate). The mother liquors from the above crystallizations are pooled and the free acid is isolated as described. dissolved in 1000 ml of ether and treated with the corresponding amount of R-(+)-a-phenylethylamine. After three-fold recrystallization from ethyl acetate there are •lc obtained 80.3 g of white crystals of melting point 20 135-136°. [a]p = +15.0° (c = 1%, methanol). Conversion of this salt according to the procedure described above yields 45.0 g of (-) 2-(2-furyl)-3-methyl- 10 20 25 30 35 butyric acid as a viscous oil of 99.5% purity. 20 [a]D as -31.1° (c a 1%. ethyl acetate). 10.5 g (0.277 mol) of lithium aluminium hydride are suspended in 100 ml of absolute ether and treated while stirring within 10 minutes with 100 ml of absolute tetrahydrofuran. To this stirred suspension are added dropwise within 6-8 hours while heating to reflux 46.7 g (0.277 mol) of (+) 2-(2-furyl)-3-methylbutyric acid in 100 ml of absolute tetrahydrofuran. Thereafter, the reaction mixture is cooled and treated slowly with a 3N hydrochloric acid solution. The organic phase is separated, washed with water, dried and evaporated under reduced pressure. The remaining oil is distilled in a high vacuum, whereby there are obtained 32 g (75%) of (R)-(+)- -2-(2-furyl)-3-methyl-l-butanol as a colourless liquid of 20 96% purity, boiling point 58°/39 Pa. [a]D = +2.5° (c = 1%, ethanol). 22 6 3 9 5 - 143 - 121.7 g (0.464 mol) of triphenylphosphine are added portionwise within 8 hours to a solution of 17.8 g (0.1154 mol) of (R)-(+)-2-(2-furyl)-3-methyl-l-butanol in 5 150 ml of carbon tetrachloride. After stirring the reaction mixture for 24 hours 500 ml of pentane are added and the precipitate formed is filtered off. After evaporation of the solvent the residue is dissolved in pentane and purified by chromatography on silica gel, 10 whereby there are obtained 5 g (92%) of 2-[(S)-(-)-l- -(chloromethyl)-2-methylpropylfuran which is used directly in the next step. A solution of 14.6 g (0.084 mol) of 2-[(S)-(-)-l-15 -(chloromethyl)-2-methylpropylfuran in 46 ml of ether are slowly added dropwise to a suspension of 3.22 g of magnesium in 12 ml of ether. The reaction mixture is stirred vigorously at room temperature overnight and thereafter cooled to -70°. 8.3 g (0.038 mol) of t-butoxy-2o carbonyl-L-leucinal in 40 ml of ether are added dropwise thereto. After completion of the addition the reaction mixture is left to stand at 0° for a further 1 hour. Thereafter, 100 ml of a saturated ammonium chloride solution are added, the organic phase is dried over 22 magnesium sulphate and the solvent is evaporated under reduced pressure. The residue obtained (16 g) is chromatographed on silica gel with a 1:4 mixture of ether and hexane, whereby there are obtained 4.8 g of t-butyl [(IS,2S.4S)-4-(2-furyl)-2-hydroxy-l-isobutyl-5-methylhexyl] 30 carbamate which is used directly in the next step. Example 70 In an analogous manner to that described in 35 Example 69, from t-butyl [(IS,2S,4S)-2-hydroxy-1-isobuty1--5-methyl-4-phenylhexyl] carbamate there was obtained [4S.5S,7S]-4-(Boc-Phe-His-NH)-2,8-dimethyl-7-phenyl-5--nonanol in the form of a thick oil. MS: 648 (M+H)+. 22 6 3 9 5 - 144 - The t-butyl [(lS,2S,4S)-2-hydroxy-l-isobutyl-5-methyl--4-phenylhexyl] carbamate used as the starting material was prepared as follows: 5 23 g of sodium in small portions are added at -35° within 90 minutes to 1500 ml of liquid ammonia. After completion of the addition 150 mg of iron-(III) nitrate.9H20 are added. To this suspension are added while stirring vigorously 150 g (1 mol) of phenylacetic 10 acid methyl ester in 500 ml of absolute tetrahydrofuran and half an hour later 100 ml (1 mol) of isopropyl iodide are added dropwise. After completion of the addition the ammonia is distilled off overnight. Water is added slowly to the liquid residue and the mixture is extracted with 15 ether. The organic extracts are washed with water, dried over sodium sulphate and evaporated under reduced pressure, whereby there are obtained 165.8 g (87%) of 2-phenyl-3-methylbutyric acid methyl ester as a yellow oil which is used directly in the next step. 20 A solution of 165.8 g (0.87 mol) of 2-phenyl-3-methyl-butyric acid methyl ester, 52.0 g (1.30 mol) of sodium hydroxide. 1200 ml of methanol and 600 ml of water is heated to reflux for one hour. After evaporation of the methanol under reduced pressure, dilution with water and acidification with conc. hydrochloric acid the aqueous solution is extracted with ether. The ethereal extracts are washed with water, dried over sodium sulphate and evaporated under reduced pressure, whereby there are 30 obtained 146.3 g (95%) of 2-phenyl-3-methylbutyric acid in the form of a yellow oil which is used directly in the next step. A solution of 146.3 g (0.82 mol) of rac. 2-phenyl-3- _c -methylbutyric acid in 820 ml of acetonitrile is treated 3D with 78.5 ml (0.615 mol) of (S)-(-)-a-phenylethylamine. The crystals thereby formed are filtered off and washed 22 6 3 9 5 - 145 - with acetonitrile. After three-fold recrystallization from acetonitrile there are obtained 88.5 g of (+)-2-phenyl-3- -methylbutyric acid as the a-phenylethylammonium salt, 20 5 melting point 198-200°. [a]D » +4.3° (c = 1%. methanol). This salt is suspended in 1000 ml of ethyl acetate and treated with 3N hydrochloric acid while cooling with ice. The ethyl acetate extracts are washed with water, dried over sodium sulphate and evaporated 10 under reduced pressure, whereby there are obtained 54.5 g of (S)-(+)-2-phenyl-3-methylbutyric acid as a light 20 yellowish oil, [a]D = +61.3° (c = 1%, chloroform). A suspension of 19.5. g (0.51 mol) of lithium 15 aluminium hydride in 750 ml of absolute ether is heated to reflux. Within 4 hours there is added dropwise thereto a solution of 54.5 g (0.307 mol) of (S)-(+)-2-phenyl-3--methylbutyric acid in 250 ml of absolute ether. After heating to reflux for a further 2 hours the suspension is 20 treated carefully with IN hydrochloric acid and the ether phase is washed with water, dilute sodium bicarbonate solution and once more with water. After drying the organic phase over sodium sulphate and evaporation under reduced pressure there are obtained 53.1 g of (S)-(+)-2-25 -phenyl-3-methylbutanol as a thick oil which is used directly in the next step. A solution of 49.3 g (0.3 mol) of (S)-(+)-2-phenyl-3- -methylbutanol in 400 ml of absolute methylene chloride is 30 treated with 80 g (0.3 mol) of triphenylphosphine. Thereafter, 53.4 g (0.3 mol) of N-bromosuccinimide are added portionwise while stirring vigorously. After 16 hours the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is 35 dissolved in hexane and purified by chromatography on silica gel. whereby there are obtained in this manner 34.9 g (51%) of (S)-(-)-2-phenyl-3-methylbromobutane as a 20 volatile oil. [a]n = -19.6° (c « 1%. chloroform). 22 6 3 9 5 - 146 - A solution of 40.9 g (0.18 mol) of (S)-(-)-2-phenyl-3--methylbromobutane in 110 ml of tetrahydrofuran and 0.5 ml of 1,2-dibromoethane is slowly added dropwise to a 5 suspension of 6.6 g of magnesium in 25 ml of ether, whereby the temperature rises to 50°. Thereafter, the reaction mixture is stirred at 50° for a further 2 hours and then cooled to -50°. Then, a solution of 13 g (0.06 mol) of N-t-butoxycarbonyl-L-leucinal in 40 ml of 10 tetrahydrofuran is added slowly. After 16 hours at room temperature the reaction mixture is treated with 200 ml of a 20% ammonium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is evaporated under reduced pressure. The residue (24.3 g) is 15 chromatographed on silica gel with a 4:1 mixture of hexane and ether, whereby there are obtained 9.3 g of t-butyl [(IS.2S.4S)-2-hydroxy-1-isobuty1-5-methy1-4-phenylhexyl] carbamate which has a melting point of 95-96° after crystallization from hexane. 20 Example 71 The following compounds were manufactured in an analogous manner to that described in Example 1: 25 - From 78 mg (0.20 mmol) of (S)-a-amino-N- -[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 57 mg (0.24 mmol) of ethoxycarbonyl-L-phenyl-alanine 57 mg of (2S.3S.5S)-l-cyclohexyl-2-30 -[(ethoxycarbonyl)-Phe-His-NH]-5-isopropyl-6- -hepten-3-ol in the form of a solid. MS: 610 (M+H) + i from 78 mg (0.20 mmol) of (S)-a-amino-N--[(IS,2S.4S)-l-(eyelohexylmethyl)-2-hydroxy-4-35 -isopropyl-5-hexenyl]imidazole-4-propionamide and 70.8 mg (0.25 mmol) of phenylacetyl-L-phenyl-alanine 97 mg of (2S.3S.5S)-l-cyclohexyl-2--[(phenylacetyl)-Phe-His-NH]-5-isopropyl-6-hepten--3-ol in the form of a solid. MS: 656 (M+H)+; 226395 - 147 - from 78 mg (0.20 mmol) of (S)-a-amino-N--[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 68 mg (0.25 mmol) of 2-pyridylcarbonyl-L-phenyl-alanine 88 mg of l-cyclohexyl-5-isopropyl-2-[(2--pyridylcarbonyl)-Phe-His-NH]-6-hepten-3-ol as a solid. MS: 643 (M+H)+: from 78 mg (0.20 mmol) of (S)-a-amino-N--[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 75 mg (0.25 mmol) of 2-phenylacetyl-L-tyrosine 110 mg of (2S.3S.5S)-l-cyclohexyl-5-isopropyl-2--[(phenylacetyl)-Tyr-His-NH]-6-hepten-3-ol as a solid. MS: 672 (M+H)+: from 78 mg (0.20 mmol) of (S)-a-amino-N--[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 72 mg (0.25 mmol) 2-pyridylcarbonyl-L-tyrosine 96 mg of (2S.3S.5S)-l-cyclohexy1-5-isopropy1-2--[(2-pyridylcarbonyl)-Tyr-His-NH]-6-hepten-3-ol as a solid. MS: 659 (M+H)+; from 175 mg (0.45 mmol) of (S)-a-amino-N--[(IS.2S,4R)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 145 mg (0.5 mmol) of 2-pyridylcarbonyl-L-tyrosine 150 mg of (S)-N-[(IS.2S.4R)-1-(cyclohexylmethyl)--2-hydroxy-4-isopropy1-5-hexenyl]-a-[(S)-p--hydroxy-a-picolinamidohydrocinnamido]imidazole--4-propionamide as a solid. MS: 659 (M+H)+; from 175 mg (0.45 mmol) of (S)-a-amino-N--[(IS.2S.4R)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide and 150 mg (0.5 mmol) of phenylacetyl-L-tyrosine 150 mg of (S)-N-[(lS.2S.4R)-l-(cyclohexylmethyl)--2-hydroxy-4-isopropy1-5-hexeny1]-a-[(S)-p--hydroxy-a-(2-phenylacetamido)hydrocinnamamido]-imidazole-4-propionamide as a solid. MS: 672 (M+H)+; - 148 - from 175 mg (0.45 mmol) of (S)-a-amino-N--[(IS.2S.4R)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]imidazole-4-propionamide and 137 mg (0.5 mmol) of 2-pyridylcarbonyl-L-phenyl-alanine 150 mg of (S)-N-[(lS.2S,4R)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-a--[(S)-a-picolinamidohydrocinnamamido]imidazole-4--propionamide as a solid, MS: 643 (M) + ; from 175 mg (0.45 mmol) of (S)-a-amino-N--[(IS,2S,4R)-1-(eyelohexylmethy1)-2-hydroxy-4--isopropy1-5-hexenyl]imidazole-4-propionamide and 141 mg (0.50 mmol) of phenylacetyl-L-phenyl-alanine 150 mg of (S)-N-[(lS,2S,4R)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropyl-5-hexeny1]-a--[(S)-a-(2-phenylacetamido)hydrocinnamamido)-imidazole-4-propionamide as a solid. MS: 656 (M+H)+; from 107 mg (0.20 mmol) of N-[(IS.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 66 mg of l-(imidazolyl)-3--propionyl-D-proline 126 mg of (S)-N-[(1S.2S.4S)--1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-[(S)-a-[(R)-l-[3-(lH-imidazol-l--yl)propionyl]-2-pyrrolidinecarboxamido]hydrocinnamamido] ]imidazole-4-propionamide as a solid. MS: 757 (M+H)+; from 111 mg (0.20 mmol) of (S)-a-[p-fluoro-L--alanyl)amino]-N-[(IS,2S,4S)-1-(cyclohexylmethyl) -2-hydroxy-4-isopropy1-5-hexenyl]imidazole-4--propionamide and 47.8 mg (0.24 mmol) of 2-(2-pyridyl)benzoic acid 120 mg of (S)-N--[(IS,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]-a-[(S)-a-[2-(2-pyridyl)-benzamido]-p-fluoro(hydrocinnamamido)]imidazole-4 -propionamide as a solid. MS: 737 (M+H)+; 22 6 39 - 149 - from 107 mg (0.20 mmol) of N-[(1S.2S,4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexeny1]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 75 mg (0.24 mmol) of Boc-D-Pro--Pro-OH 122 mg of (2S.5S)-2-(Boc-D-Pro-Pro-Phe--His-NH)-1-cyclohexy1-5-isopropyl-6-hepten-3-ol as a solid. MS: 832 (M+H)+. from 269 mg (0.6 mmol) of N-[(lS.2S.4R)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-a--(3-phenyl-L-alanyl)imidazole-4-propionamide and 187 mg (0.6 mmol) of Boc-D-Pro-Pro-OH 400 mg of t-butyl (R)-2-[[(s)-2-[[(S)-a-[[(S)-l--[[(lS.2S.4R)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexeny1]carbamoyl]-2-imidazo1-4--ylethylJcarbamoyl]phenethyl]carbamoyl]-1--pyrrolidinyl]carbonyl]-l-pyrrolidinecarboxylate as a solid. MS: 832 (M+H)+. from 269 mg (0.5 mmol) of N-[(IS,^S.4R)-1-(cyclohexylmethyl)-2-hydr oxy-4-isopr opy 1-5-hexenyl ]-a--(3-phenyl-L-alanyl)imidazole-4-propionamide and 260 mg (0.6 mmol) of t-butoxycarboriyl-D-phenyl-glycine 110 mg of t-butyl [[(R)-a-[[(S)-a--[[(S)-l-[[(IS,2S,4R)-1-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexeny1]carbamoyl]-2--imidazo1-4-ylethyl]carbamoyl]phenethyl]carbamoyl] benzyl] carbamate as a solid, MS 771 (M+H)+. from 269 mg (0.5 mmol) of N-[(IS.2S.4R)-1-(cyclohexylmethyl ) -2-hydr oxy- 4- isopr opy 1-5-hexenyl ]-a--(3-phenyl-L-alanyl)imidazole-4-propionamide and 119 mg (0.6 mmol) of 2-(2-pyridyl)benzoic acid 290 mg of (S)-N-[(IS.2S,4R)-1-(eyelohexylmethyl)--2-hydroxy-4-isopropy1-5-hexenyl]-a-[(S)-a-[2--(2-pyridyl)benzamido]hydrocinnamamido]imidazole-4 -propionamide as a solid. MS: 719 (M+H)+. 226395 - 150 - from 107 mg (0.20 mmol) of N-[(1S.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexeny1]-a-(3-pheny1-L-alanyl)imidazole-4--propionamide and 75 mg (0.24 mmol) of Boc-Pro--Pro-OH 137 mg of (2S.3S.5S)-2-(Boc-Pro-Pro-Phe--His-NH)-l-cyclohexy1-5-isopropy1-6-hepten-3-ol as a solid. MS: 832 (M+H)+; from 107 mg (0.20 mmol) of N-[(1S.2S.4R)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexeny1]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 71 mg (0.24 mmol) of IVA-D-Pro--L-Pro-OH 130 mg of (S)-N-[(IS.2S.4R)-1-(cyclohexylmethyl ) -2-hydr oxy-4- isopr opy 1-5- hexeny 1 ]-a--[[N-[l-[(l-isovaleryl-D-prolyl)-L-prolyl]-3--phenyl-L-alanyl]amino]imidazole-4-propionamide as a solid. MS: 816 (M+H)+; from 107 mg (0.20 mmol) of N-[(1S.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 67 mg (0.24 mmol) of N-t-butoxycarbonyl-N-methyl-L-phenylalanine 100 mg t-butyl [ (S)-ct-[ [ (S)-a-[ [ (S)-l--[[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]carbamoyl]-2-imidazo1-4--ylethyl]carbamoyl]phenethyl]carbamoyl]phenethyl]-methyl carbamate as a solid, MS: 799 (M+H)+; from 107 mg (0.20 mmol) of N-[(1S.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 71 mg (0.24 mmol) of IVA-D-Pro--Pro-OH 141 mg of (2S.3S.5S)-l-cyclohexyl-2-[(3--methylbutyryl)-D-Pro-Pro-Phe-His-NH]-5-isopropyl--6-hepten-3-ol as a solid. MS: 816 (M+H)+; from 107 mg (0.20 mmol) of N-[(1S,2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl)-a-(3-phenyl-L-alanyl)imidazole-4- 226J9S - 151 - -propionamide and 74 mg (0.24 mmol) of Boc-(A3--deshydro)-Pro-Pro-OH 125 mg of (2S.3S.5S)-2--[[[(S)-l-Boc-3-pyrrolin-2-yl]carbonyl]-Pro-Phe--His-NH]-1-cyclohexy1-5-isopropy1-6-hexen-3-ol as a solid. MS: 830 (M+H)+: from 107 mg (0.20 mmol) of N-[(1S.2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 75 mg (0.24 mmol) of Boc-Pro-D--Pro-OH 135 mg of (2S»3S.5S)-2-(Boc-Pro-D-Pro--Phe-His-NH)-1-cyclohexy1-5-isopropyl-6-hepten-3--ol as a solid. MS: 832 (M+H)+; from 107 mg (0.20 mmol) of N-[(1S.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 75 mg (0.24 mmol) of Boc-D-Pro--D-Pro-OH 133 mg of (2S.3S,5S)-2-(Boc-D-Pro-D--Pro-Phe-His-NH)-1-cyclohexy1-5-isopropyl-6-hepten--3-ol as a solid. MS: 832 (M+H)+; from 110 mg (0.20 mmol) of (S)-a-(Phe-methyl-amino)-N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and 75 mg (0.24 mmol) of Boc-D-Pro-Pro-OH 87 mg of (S)-a-[Boc-D-Pro-Pro-Phe-N(CH3)]-N--[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide as a solid. MS: 846 (M+H)+; from 107 mg (0.20 mmol) of N-[(1S.2S.4S)-1- -(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5- -hexenyl]-a-(3-pheny1-L-alanyl)imidazole-4- -propionamide and 55 mg (0.24 mmol) of (S)-N-t- -butoxycarbonyl-piperidine-2-carboxylic acid 127 mg of (2S.3S.5S)-1-[[[(S)-l-Boc-2- -piperidinyl]carbonyl]-Phe-His-NH]-1-cyclohexy1-5- -isopropyl-6-hepten-3-ol as a solid. MS: 749 (M+H)+; 226395 - 152 - from 54 mg (0.10 mmol) of N-[(lS,2S.4S)-l-(cyclo-hexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-a--(3-phenyl-L-alanyl)imidazole-4-propionamide and 5 49 mg (0.12 mmol) of Boc-D-Pro-D-Pro-Pro-OH 57 mg of (2S.3S,5S)-2-(Boc-D-Pro-D-Pro-Pro-Phe-His-NH)--l-cyclohexyl-5-isopropyl-6-hepten-3-ol as a solid. MS: 927 (M+H)+; from 107 mg (0.20 mmol) of N-[(IS.2S.4S)-1-10 -(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5- -hexeny1]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 56 mg (0.24 mmol) of (R)-N-t--butoxycarbony1-thiazolidine-2-carboxylie acid 126 mg of (2S.3S,5S)-2-[[[(R)-3-Boc-4-15 -thiazolidiny1]carbony1-Phe-His-NH]-1-cyclohexy1-5- -isopropyl-6-hepten-3-ol as a solid. MS: 753 (M+H)+; from 80 mg (0.123 mmol) of (2S.3S.5S)-1-[[[(S)-2--piperidinyl]carbonyl]-Phe-His-NH]-1-cyclohexy1-5-2o -isopropyl-6-hepten-3-ol and 64 mg (0.30 mmol) of Boc-D-Pro-OH 106 mg of (2S.3S.5S)-2-(Boc-D-Pro--Pip-Phe-His-NH)-1-cyclohexy1-5-isopropy1-6-hepten--3-ol as a solid, MS: 846 (M+); from 107 mg (0.20 mmol) of N-[(1S,2S.4S)-1-25 -(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5- -hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 79 mg (0.24 mmol) of (R)-N-t--butoxycarbony1-thiazolidinyl-l-carbony1-proline 163 mg of (2S.3S,5S)-2-[[[(R)-3-BOC-4-30 -thiazolidiny1]carbonyl]-Pro-Phe-His-NH]-1-cyclo- hexyl-5-isopropyl-6-hepten-3-ol as a solid, MS: 850 (M+H)+; from 107 mg (0.20 mmol) of N-[(1S,2S.4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5-35 -hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4- -propionamide and 71 mg (0.24 mmol) of 2-(2-pyridyl)benzoic acid 140 mg of (2S,3S,5S)-1- 22630 - 153 - -eyelohexy1-5-isopropyl-2-[[2-(2-pyridyl)benzoylJ- -Pro-Phe-His-NHJ-6-hepten-3-o1 in the form of the dihydrochloride. MS: 816 (M+H)+; from 107 mg (0.20 mmol) of (N-[(IS.2S.4S)-1- -(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5- -hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4- -propionamide and 57 mg (0.24 mmol) of 3-dimethy1-3-(1-imidazolyl)propionyl-Pro-Pro-OH 160 mg of (2S.3S,5S)-1-cyclohexy1-2[(3,3- -dimethyl-3-imidazo1-1-ylpropionyl)-Pro-Pro-Phe- -His-NH]-5-isopropyl-6-hepten-3-ol as a solid, MS: 882 (M+H)+; from 107 mg (0.20 mmol) of (N-[(1S,2S,4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenylJ-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 77 mg (0.24 mmol) of N-(l-imidazolyl)acetyl-D-Pro-Pro-OH 160 mg of (2S.3S.5S)-1-cyclohexy1-2-[(imidazol-l-ylacetyl)-D--Pro-Pro-Phe-His-NH]-5-isopropyl-6-hepten-3-ol in the form of the dihydrochloride as a solid, MS: 840 (M+H)+; from 107 mg (0.20 mmol) of (N-[(1S,2S,4R)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropyl-5--hexenylJ-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 77 mg (0.24 mmol) of N-(l-imidazolyl)acetyl-D-Pro-Pro-OH 148 mg of (2S,3S.5R)-l-cyclohexyl-2-[(imidazol-l-ylacetyl)-D--Pro-Pro-Phe-His-NH]-5-isopropyl-6-hepten-3-ol in the form of the dihydrochloride, as a solid, MS: 840 (M+H)+; from 107 mg (0.20 mmol) of (N-[(1S.2S,4S)-1--(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]-a-(3-phenyl-L-alanyl)imidazole-4--propionamide and 83 mg (0.24 mmol) of benzyloxy-carbonyl-Pro-Pro-OH 155 mg of (2S.3S.5S)-2--(benzyloxycarbony1-Pro-Pro-Phe-His-NH)-1-cyclo-hexyl-5-isopropyl-6-hepten-3-ol as a solid. MS: 866 (M+H)+; 22 6 3 95 - 154 - The (S)-a-(Phe-methylamino)-N-t(IS.2S.4S)-1-(eyelohexy lme thyl) -2-hydr oxy- 4- isopr opy 1-5-hexenyl] imidazole-4--propionamide used as the starting material was prepared as follows: A mixture of 1.50 g (4 mmol) of N-a-N-im-di-t--butoxycarbonyl-N-a-methylhistidine. 1.0 g (3.4 mmol) of (S.S.S)-6-amino-6-cyclohexylmethyl-4-isopropyl-l-hexen-5-ol hydrochloride. 1.33 g (3.5 mmol) of HBTU, 7.8 ml of N-methylmorpholine and 20 ml of dimethylformamide is stirred at room temperature for 4 hours. Thereafter, the solvent is evaporated under reduced pressure and the oily residue is dissolved in ether. The organic phase is washed firstly with a sodium bicarbonate solution and thereafter with saturated sodium chloride solution and. after drying over sodium sulphate, is evaporated under reduced pressure, whereby there are obtained 2.1 g of (S)-3-(t-butoxycarbonyl)-a-[1-(t-butoxycarbonyl)-N-methyl-formamido]-N-[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide which is used directly in the next step. 2.1 g of (S)-3-(t-butoxycarbonyl)-a-[l-(t-butoxy-carbonyl)-N-methylformamido]-N-[(IS.2S,4S)-1-(cyclohexylmethyl )-2-hydroxy-4-isopropy1-5-hexenyl]imidazole-4-propionamide are dissolved in 30 ml of 3N hydrogen chloride in dioxan and the mixture is left to stand at room temperature for 5 hours. Thereafter. 500 ml of ether are added and the precipitate formed is filtered off. Then, the precipitate is washed with ether and dissolved in water. Solid sodium bicarbonate is added to the aqueous solution and the mixture is extracted several times with ethyl acetate, whereby there is obtained 0.85 g of (S)-a-(N-methyIformamido)-N-[(IS.2S.4S)-1-(cyclohexylmethyl ) -2-hydr oxy- 4 -isopr opy 1-5-hexenyl ] imidazo le-4 -propionamide which is used directly in the next step. 22 6395 - 155 - A mixture of 0.85 g (2.1 mmol) of (S)-a-(N-methyl-formamido)-N-[(IS.2S.4S)-l-(eyelohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl]imidazole-4-propionamide, 0.67 g (2.5 mmol) of N-t-butoxycarbonylphenylalanine. 0.84 g (2.2 mmol) of HBTU. 0.3 ml of N-methylmorpholine and 20 ml of dimethylformamide is left to stand at room temperature for 60 hours and thereafter poured into a saturated sodium bicarbonate solution. The precipitate thereby formed is filtered off and dissolved in ethyl acetate. The organic solution is dried over magnesium sulphate and evaporated under reduced pressure. The residue remaining is triturated with hexane and filtered off. whereby there are obtained 1.35 g of (S)-a-(Boc-Phe-methylamino)-N--[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide in the form of a powder which is used directly in the next step. 1.3 g of (S)-a-(Boc-Phe-methylamino)-N-[(1S.2S,4S)--1-(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-imidazole-4-propionamide are dissolved in 30 ml of 3N hydrogen chloride in dioxan and the mixture is left to stand at room temperature for 1 hour. Thereafter. 200 ml of ether are added and the mixture is left to stir at room temperature for 16 hours. The precipitate formed is filtered off. washed with ether and dissolved in water. Thereafter, solid sodium bicarbonate is added to the aqueous solution and the mixture is then extracted several times with ethyl acetate, whereby there is obtained 0.97 g of (S)-a-(Phe-methylamino)-N-[(1S.2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenylJ-imidazole-4-propionamide which is used directly in the next step. The (2S,3S,5S)-l-[[[(S)-2-piperidinyl]carbonylJ-Phe--His-NH]-l-cyclohexyl-5-isopropyl-6-hepten-3-ol which is also used as a starting material was prepared by cleaving 22 6 3 9 5 - 156 - off the t-butoxycarbonyl group from (2S.3S.5S)-l-[[[(S)-l--Boc-2-piperidinyl]carbony1-Phe-His-NH]-1-cyclohexy1-5--isopropyl-6-hepten-3-ol by means of hydrochloric acid in 5 dioxan and was used directly in the next step. Example 72 A mixture of 31 mg (0.21 mmol) of N-cyano-dimethyl-10 dithiocarbamate. 107 mg (0.20 mmol) of N-[(IS.2S,4S)-1- -(eyelohexylmethyl]-2-hydroxy-4-isopropy1-5-hexeny1]-a-(3--phenyl-L-alanyl)imidazole-4-propionamide and 1 ml of methanol is left to stand at room temperature for 24 hours. Thereafter, the solvent is evaporated under 15 reduced pressure and the residue is digested with a 1:1 mixture of hexane and ether, whereby there are obtained 112 mg of (S)-N-[(lS.2S,4S)-l-(cyclohexylmethyl)-2--hydroxy-4-isopropyl-5-hexenyl]-a-[[N-[(cyanoimino)-(methylthio)methyl]-3-phenyl-L-alanyl]amino]imidazole-4-20 -propionamide as a solid. MS: 636 (M+H)+. Example 73 100 mg of (2S.5S)-2-(Boc-D-Pro-Pro-Phe-His-NH)-l-25 -cyclohexyl-5-isopropyl-6-hepten-3-ol are dissolved in 3 ml of 3.2N hydrogen chloride in dioxan, the solution is left to stand for 1 hour and thereafter the desired product is precipitated by the addition of ether. The precipitate is filtered off and dried under reduced 30 pressure, whereby there are obtained 100 mg of [2S.3S.5S]- -1-cyclohexy1-2-(D-Pro-Pro-Phe-His-NH)-5-isopropyl-6-hepten--3-ol in the form of the dihydrochloride as a solid. MS: 732 (M+H)+. 35 22 6 39 - 157 -Example 74 41 mg (0.05 mmol) of (2S.3S.5S)-l-cyclohexyl-2-[(3-5 -methylbutyryl)-D-Pro-Pro-Phe-His-NH]-5-isopropy1-6-hepten--3-ol are dissolved in 5 ml of methanol and hydrogenated in the presence of 20 mg of palladium-on-carbon (5%). After completion of the hydrogen uptake the catalyst is filtered off and the solvent is evaporated under reduced 10 pressure. Trituration of the residue with hexane and drying yields 34 mg of (2S.3S,5S)-l-cyclohexyl-5--isopropy1-2-(isovaleryl-D-Pro-Pro-Phe-His-NH)-3-heptanol as a solid. MS: 818 (M+H)+. 15 The above hydrogenation can also be used to produce the corresponding isomeric compound when it is carried out under the following conditions: 200 mg of starting material in 15 ml of methanol are hydrogenated in the presence of 50 mg of palladium-on-2o -carbon (5%) and thereafter the mixture is worked-up as usual, whereby there are obtained 184 mg of (2S.3S.5R)-1--cyclohexy1-5-isopropy1-2-(isovaleryl-D-Pro-Pro-Phe-His-NH) -3-heptanol as a solid. MS: 818 (M+H)+. 25 Example 75 80 mg (0.25 mmol) of 3-(l-imidazolyl)propionyl-pro--Pro-OH, 110 mg (0.20 mmol) of (S)-a-(Phe-methylamino)--N-[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5 30 -hexenyl]imidazole-4-propionamide. 84 mg (0.22 mmol) of HBTU. 0.03 ml of N-methylmorpholine and 2 ml of dimethyl-formamide are left to stand at room temperature for 16 hours. Thereafter, the reaction mixture is poured into 50 ml of a 5% sodium carbonate solution and the milky 35 suspension is extracted several times with ethyl actate. The organic extracts are dried over magnesium sulphate and 22 6 3 9 5 - 158 - evaporated under reduced pressure. The residue is dissolved in 10 ml of ethyl acetate and the solution is treated with 1.5 ml of a 3.ON solution of hydrogen 5 chloride in dioxan. The precipitate thereby formed is filtered off and dried, whereby there are obtained 143 mg of (S)-N-[(IS,2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropy1-5-hexenyl]-a-[[3-(imidazol-l-yl)propionyl]-D--Pro-Pro-Phe-N-(methyl)]imidazole-4-propionamide hydro-10 chloride as a solid, MS: 868 (M+H)+. In an analogous manner to that described above, from 77 mg (0.24 mmol) of 2-(1-imidazolyl)acetyl-Pro-Pro-OH and 110 mg of (S)-a-(Phe-methylamino)-N-[(lS.2S.4S)-l-15 -(eyelohexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]- imidazole-4-propionamide there were manufactured 155 mg of (S)-N-[(IS.2S.4S)-1-(eyelohexylmethyl)-2-hydroxy-4--isopropy1-5-hexeny1]-a-[(imidazol-l-ylethyl)-D-Pro-Pro--Phe-N-(methyl)]imidazole-4-propionamide dihydrochloride 2o as a solid, MS: 840 (M+H)+. Example 76 105 mg of (S)-N-[(lS,2S,4S)-l-(cyclohexylmethyl)-2-25 -hydroxy-4-isopropy1-5-hexenyl]-a-[[3-(imidazol-1-yl)- propionyl]-D-Pro-Pro-Phe-N-(methyl)]imidazole-4-propion-amide hydrochloride are dissolved in 15 ml of methanol and hydrogenated in the presence of 50 mg of palladium-on--carbon. After completion of the hydrogen uptake the 30 catalyst is filtered off and the filtrate is evaporated to dryness. The residue is triturated with ether and filtered off. whereby there are obtained 65 mg of (2S.3S.5S)-1--cyclohexy1-2-[(3-imidazol-1-ylpropionyl)-D-Pro-Pro-Phe-His--NH]-5-isopropyl-3-heptanol dihydrochloride as a solid. 35 MS: 856 (M+H)+. 22 6 39 5 - 159 - Example 77 A sterile filtered aqeous solution of (S)-a-[(R)-2-5 -benzy1-5.5-dimethyl-4-oxohexanamido3-N-[(IS,2S.4S)-1--(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5-hexenyl]-imidazole-4-propionamide is mixed while warming with a sterile gelatine solution, which contains phenol as a preserving agent, under aseptic conditions so that 1.0 ml 10 of solution has the following composition: (S)-a-[(R)-2-Benzyl-5.5-dimethyl-4-oxohexanamido]-N--[(IS.2S.4S)-l-(cyclohexylmethyl)-2-hydroxy-4-isopropy1-5--hexenyl]imidazole-4-propionamide 3.0 mg 15 Gelatine 150.0 mg Phenol 4.7 mg 20 Distilled water to 1.0 ml The mixture is filled into vials of 1.0 ml under aseptic conditions. 25 Example 78 5 mg of (S)-a-[(R)-2-benzyl-5.5-dimethyl-4-oxohexan-amido3-N-[(IS.2S.4S)-1-(cyclohexylmethyl)-2-hydroxy-4--isopropyl-5-hexenyl3imidazole-4-propionamide are 30 dissolved in 1 ml of an aqueous solution 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 35 or 1 ml of physiological saline. The solution is used intramuscularly or intravenously. This formulation can also be filled into double chamber injection ampoules. </div>

NZ226395A 1987-10-06 1988-09-29 Renin-inhibiting amino acid derivatives and pharmaceutical compositions NZ226395A (en)

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FI (1)	FI884598A (en)
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IL (1)	IL87871A0 (en)
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AU595309B2 (en) *	1986-05-09	1990-03-29	Dainippon Pharmaceutical Co. Ltd.	Tripeptide derivatives
US4895834A (en) *	1986-12-15	1990-01-23	Warner-Lambert Company	Renin inhibitors III
US5023236A (en) *	1988-04-07	1991-06-11	Corvas, Inc.	Factor VII/VIIA active site inhibitors
EP0391180A3 (en) *	1989-04-04	1991-04-03	F. Hoffmann-La Roche Ag	Peptide derivatives of amino acids having a renin-inhibiting effect
CA2012901A1 (en) *	1989-04-05	1990-10-05	Quirico Branca	Amino acid derivatives
NZ235234A (en) *	1989-09-12	1992-12-23	Hoechst Ag	Renin-inhibiting amino acid derivatives and pharmaceutical compositions thereof
DE4008403A1 (en) *	1990-03-16	1991-09-19	Merck Patent Gmbh	GLYKOLSAEUREDERIVATE
US5516784A (en) *	1991-08-13	1996-05-14	Schering Corporation	Anti-HIV (AIDS) agents
US5422349A (en) *	1992-08-14	1995-06-06	G. D. Seale & Co.	Morpholino-oxazinyl-terminated alkylamino ethynyl alanine amino diol compounds for treatment of hypertension
WO1994017096A1 (en) *	1993-01-17	1994-08-04	Schering Corporation	Peptides having anti-hiv activity
US5563127A (en) *	1993-03-24	1996-10-08	The Dupont Merck Pharmaceutical Company	Boronic acid and ester inhibitors of thrombin
FR2741066B1 (en) *	1995-11-14	1997-12-12	Rhone Poulenc Rorer Sa	NEW TRANSFECTION AGENTS AND THEIR PHARMACEUTICAL APPLICATIONS
FR2752422B1 (en) *	1996-08-16	1998-11-06	Lipha	PHARMACEUTICAL COMPOSITION CONTAINING 4-OXO-BUTANOIC ACIDS
ID27933A (en) *	1998-05-12	2001-05-03	Warner Lambert Co	COMBINED PROTEIN FARNESILTRANS FERASE AND HMG-COA REDUCTURE INHIBITORS AND ITS USE TO TREAT CANCER
EP2494993B1 (en) *	2007-05-04	2018-08-01	Marina Biotech, Inc.	Amino acid lipids and uses thereof
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US4652551A (en) *	1984-06-22	1987-03-24	Abbott Laboratories	Renin inhibiting compounds
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IL87871A0 (en)	1989-03-31
ZA887322B (en)	1989-06-28
FI884598A (en)	1989-04-07
NO884434L (en)	1989-04-07
YU185188A (en)	1990-12-31
AU627156B2 (en)	1992-08-20
MC1985A1 (en)	1989-11-23
PT88679A (en)	1989-07-31
HUT49322A (en)	1989-09-28
FI884598A0 (en)	1988-10-06
EP0310918A2 (en)	1989-04-12
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DK523288D0 (en)	1988-09-20
AU2330788A (en)	1989-06-08

Publication	Publication Date	Title
US5278148A (en)	1994-01-11	Amino acid derivatives useful for treating high blood pressure
US5688946A (en)	1997-11-18	Amino acid derivatives having renin inhibiting activity
FI105024B (en)	2000-05-31	A process for the preparation of therapeutically useful N- (amidinobenzoyl or amidinopyridylcarbonyl) -alpha-amino acid derivatives
US4692458A (en)	1987-09-08	Anti-hypertensive agents
NZ226395A (en)	1991-12-23	Renin-inhibiting amino acid derivatives and pharmaceutical compositions
EP0184550A2 (en)	1986-06-11	5-Amino-4-hydroxy valeryl amide derivatives
JPH03386B2 (en)	1991-01-07
US5250517A (en)	1993-10-05	Renin inhibiting compounds
EP0307837A2 (en)	1989-03-22	Renin-inhibiting peptidyl heterocycles
JP7132125B2 (en)	2022-09-06	Neuropeptide S receptor (NPSR) agonist
KR20010024220A (en)	2001-03-26	New NPY Antagonists
US5140011A (en)	1992-08-18	Amino acid derivatives which have renin inhibiting activity
WO1999055726A1 (en)	1999-11-04	Certain thiol inhibitors of endothelin-converting enzyme
HU205770B (en)	1992-06-29	Process for producing renin inhibiting dipeptide derivatives and pharmaceutical compositions comprising same
DE60215368T2 (en)	2007-08-16	PYRANDERIVATES AS INHIBITORS OF ACE AND NEP
NZ242311A (en)	1994-12-22	Amino acid derivatives useful in treating high blood pressure
US20020082218A1 (en)	2002-06-27	Certain thiol inhibitors of endothelin-converting enzyme
US5198426A (en)	1993-03-30	Renin inhibitors containing c-terminal dihydroxy amides
US5426103A (en)	1995-06-20	Certain macrocyclic lactam derivatives
CA2013475A1 (en)	1990-10-04	Amino acid derivatives
JPH06503315A (en)	1994-04-14	Renin-inhibitory peptides of the cyclohexylstatin type, their preparation and their use in medicines
IE65539B1 (en)	1995-11-01	Trifluoromethyl mercaptan and mercaptoacyl derivatives and method of using same
US4698355A (en)	1987-10-06	Anti-hypertensive agents
US4690938A (en)	1987-09-01	Anti-hypertensive agents
US4690940A (en)	1987-09-01	Anti-hypertensive agents