CA2015070A1 - Dipetide derivatives having enzyme-inhibitory action - Google Patents

Abstract

Abstract of the disclosure: HOE 89/F 128 Dipeptide derivatives having enzyme-inhibitory action The present invention relates to compounds of the formula I

Description

HOECHST ARTIENGESELLSCHAFT HOE 89/F 128 Dr.MY/gm ;

De8cription 201~7~

DipQptide derivatives having enzy e-inhibitory action The invention relates to dipeptide derivatives which inhibit the action of the natural enzyme renin and to processes for their preparation and use and to pharma-ceutical preparations containing them. In ~P-A 0,255,082, dipeptide derivatives are described which carry N-ter-minal cycloalkylcarbonyl and cycloalkyl-alkylcarbonyl substituents. In WO 88/05050, aminodiol derivatives having renin-inhibitory action are described.

Surpri~ingly, it has now been found that substituted cycloalkyl and cycloalkyl-alkyl derivatives contribute to the considerable improvement of the action in vivo and to the increased absorption of the compound.

The invention relates to compounds of the formula I

Ra-W-A-B-NH-CH-CH-CH-R4 (I) in which R' denotes ( C3-C~) -cycloalkyl, (C~-Cl0)-bicycloalkyl, (C~-C~)-tricycloalkyl, ( C3-C~ ) -cycloalkyl-(cl-c6)-alkyl, (C~-Cl0)-bicycloalkyl-(Cl-C6)-alkyl and (C~-C~)-tricycloalkyl-(Cl-C6)-alkyl, in which in each case the cycloalkyl, bicycloalkyl and tricycloalkyl substituents can be substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cl-C6)-alkoxy, (Cl-C6)-alkyl, carboxyl, (Cl-C6)-alkoxycarbonyl, carbamoyl, carbo~ymethoxy, amino, (Cl-C0)-monoalkyl-amino, (Cl-C6)-dialkylamino, amino-(Cl-C6)-alkyl, (Cl-C6)-alkylamino-(Cl-C6)alkyl, di-(Cl-C6)-alkylamino-(cl-c6)-alkyl~ amidino, hydroxamino, hydroximino, hydrazono, imino, guanidino, (Cl-C6)-alkyloxy-- 2 - 201 ~ 07 ~

sulfonyl, (C1-C~)-alkyloxysulfenyl, trifluoromethyl, (Cl-C~)-alkoxycarbonylamino or (C6-Cl2)-aryl-(C1-C4)-alkoxycarbonylamino;
W stands for -CO-, -O-CO- or -SO2-, R2 denotes hydrogen, (C1-Cl0)-alkyl, (C~-C~)-cycloalkyl, ( C~-C7 ) -cycloalkyl-(C1-C~)-alkyl~ (C~-C1~)-aryl or ( CB_C1~ ) -aryl-(C1-C~)alkyl~

R3 denotes hydrogen, (Cl-C10)-alkyl, (C6-Cl~)-arYl-(C6-C1~)-aryl-(Cl-Cj)-alkyl, hydroxyl or amino, R4 denotes a radical of the formula II

(CH2)~-cHRs-D (II) where R5 stands for hydrogen, (C1-C,)-alkyl, (C1-C5)-alkoxy, (Cl-C5)-alkylthio, (Cl-Cs)-alkylamino, hydroxyl, azido, fluorine, chlorine, bromine or iodine, D denotes a radical Het, where Het denotes a 5- to 7-membered heterocyclic ring which can be fused to benzene, aromatic, partially hydrogenated or completely hydro-genated, which can contain one or two identical or different radicals from the group N, O, S, NO, SO or SO2 as heteroatoms and which can be substituted by one or two identical or dif-ferent radicals from the group comprising (Cl-C~)-alkyl,(Cl-C~)-alkoxy,hydroxyl,halogen, amino, mono- or di-(C1-C~)-alkyl~mino or CF3, and m denotes 0, l, 2, 3 or 4;

A and B independently of one another denote a radical of an amino acid linked at the nitrogen terminus to R^-~ 3 ~ 2 0 ~
W or A and at the carbon terminus to B or NH-CHR2-CHoH-CHR9-R~ from the series comprising phenyl-alanine, histidine, tyro~ine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, ~-2-thienylalanine, ~-3-thienyl-alanine, ~-2-furylalanine, ~-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridyl-alanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine,0-methyltyrosine,0-benzyltyrosine, 0-tert.-butyltyrosine, phenylglycine, l-naphthyl-alanine, 2-naph*hylalanine, 4-nitrophenylalanine, norvaline,0-2-benzotb]thienylalanine,~-3-benzo[b]-thienylalanine, 2-fluorophenylalanine, 3-fluoro-phenylalanine, 4-pyridylalanine, 4-fluorophenyl-alanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, 0-dimethyl-DOPA, N-methyl-histidine, 2-amino-4-(2-thienyl)-butyric acid, 2-amino-4-(3-thienyl)-butyric acid, 3-(2-thienyl)-serine,(Z)-dehydrophenylalanine,(E)-dehydsophenyl-alanine,l,3-dioxolan-2-ylalanine,N-pyrrolylalanine and 1-, 3- or 4-pyrazolylalanine, and their physiologically tolerable salts.

The chiral centers in the compounds of the formula I can have the R-, S- or R,S-configuration.

Alkyl can be straight-chain or branched. The same applies to r~dicals derived therefrom, such as, for example, alkoxy, alkylthio, alkylamino, dialkylamino, alkanoyl and aralkyl. (C3-C~)-Cycloalkyl is understood a~ meaning cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl and cyclooctyl. (C~-C10)-Bicycloalkyl or (C~-C~)-tricycloalkyl are understood as meaning an isocyclic aliphatic, non-aromatic radical which can optionally contain unsymmetrically distributed double bonds, and _ 4 _ 2 01 5 0~
which can optionally also be substituted with open-chain aliphatic ~ide chains. The two or three rings as com-ponents of a radical of thi~ type are condensed or linked in a spiro fashion and linked via a ring carbon atom or a side chain carbon atom. Examples of these radicals are bornyl, norbornyl, pinanyl, norpinanyl, caranyl, norcaranyl, thu~anyl, adamantyl, bicyclo(3.3.0)octyl, bicyclo(l.l.O)butyl and spiro(3.3)heptyl substituents.

If the cyclic compounds mentioned carry more than one substituent, these can be both cis and trans to one another.

(C6-C,4)-aryl is, for example, phenyl, naphthyl, bipheny-lyl or fluorenyl; phenyl is preferred. ~he same applies to radicals derived therefrom, such as, for example, aryloxy, aroyl, aralkyl and aralkyloxy. Aralkyl is under3tood as meaning an unsubstituted or substituted (C6-C14)-aryl radical linked to (C,-C6)-alkyl, such as, for example, benzyl, ~- and ~-naphthylmethyl, halobenzyl and alkoxybenzyl, aralkyl, however, not being limited to the radicals mentioned.

A radical Het in the sense of the preceding definition is, for ex~mple, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinox-alinyl, ~-carbolinyl or a derivative of these radicals which is fused to benzene, cyclopentane, cyclohexane or cycloheptane. This heterocycle may be substituted on a nitrogen atom by oxido, (C~-C6)-alkyl, for example methyl or ethyl, phenyl or phenyl-(C,-C~)-alkyl, for example benzyl, and/or on one or more carbon atoms by (Cl-C~)-alkyl, for example methyl, phenyl, phenyl-(Cl-C~)-alkyl, for example benzyl, halogen, for example chlorine, hydroxyl, (Cl-C~)-alkoxy, for example methoxy, phenyl-(cl-c4)-alkoxy~ for example benzyloxy, or oxo and can be partially ~aturated and i8 ~ for example, 2- or 3-pyr-rolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-- 5 - 2~
pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimid-azolyl, for example l-methyl-2-, 4- or 5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 1-oxido-2-, 3- or 4-pyridino, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, for example l-methyl-, 5-methyl-, 5-methoxy, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or 3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cycloheptatb]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquino-lyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxszolyl, 2-benzothiazolyl, benz[e]-indol-2-yl or ~-carbolin-3-yl.

Partially hydrogenated or completely hydrogenated hetero-cyclic rings are, for example, dihydropyridinyl, pyr-rolidinyl, for example 2-, 3- or 4-N-methylpyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino and tetrahydrothiophenyl.

- Salts of compounds of the formula I are to be understood as meaning, in particular, pharmaceutically utilizable or non-toxic salts.

Such salts are formed, for example, from compounds of the formula I which contain acidic groups, for example carboxyl, with alkali metals or alkaline earth metals, such as Na, K, Mg and Ca, and also with physiologically tolernble organic amines, such as, for example, triethyl-amine and tri-(2-hydroxyethyl)amine.

Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids, such as, for example, hydro-chloric acid, sulfuric acid or pho~phoric acid and withorganic carboxylic or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.

- 6 - 2 0 ~ 5 0 ~ ~
Preferred compounds of the formula I are those in which R' and W are as defined on page 1;
R2 denotes isobutyl, benzyl or cyclohexylmethyl;

R3 denotes hydrogen, ( C~-C5) -alkyl, (Cff-C10)-aryl, S (C6-C1~)-aryl-(C,-C~j-alkyl or hydroxyl;

R~ denotes a radical of the formula II, in which R5 stands for hydrogen, (C~-C~)-alkyl, (C1-C~)-alkoxy, (Cl-C~)-alkylthio, (C1-C~)-alkylamino, hydroxyl, azido, fluorine, chlorine, bromine or iodine, D is defined as the radical Het on page 2, and m denotes 0, 1 or 2; and A and B independently of one another denote a bivAlent radical from the series comprising ; 15 phenylalanine, histidine, tyrosine, tryptophan, ; methionine, leucine, isoleucine, asparagine, aspar-tic acid, ~-2-thienylalanine, ~-3-thienylalanine, ~-2-furylalanine, ~-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methi-onine sulfoxide, 2-pyridylalanine, 4-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylgly-cine, im-methylhistidine, 0-methyltyrosine, 0-benzyltyrosine, 0-tert.-butyltyrosine, phenylgly-cine, l-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, norleucine,cysteine, S-methylcysteine, N-methylhistidine, 1,2,3,4-tetra-hydroisoquinoline-3-carboxylicacid,homophenylalan-ine, 2-amino-4-(2-thienyl)-butyric acid, 2-amino-4-(3-thienyl)-butyric acid, 3-(2-thienyl)-serine, (Z)-dehydrophenylalanine,(E)-dehydrophenylalanine,1,3-dioxolan-2-ylalanine, N-pyrrolylalanine and 1-, 3-or 4-pyrazolylalanine, and their physiologically tolerable salts.

- 7 - 2 01 ~ 07 ~
Particularly preferred compounds of the formula I are those in which R' denotes (C~-C6)-cycloalkyl and tC~-C6)-cycloalkyl-(Cl-C2)-alkyl, in which in each case the cycloalkyl S substituent can be sub6tituted by one or two identi-cal or different radicals from the series comprising hydroxyl, (Cl-C~)-alkoxy, (Cl-C2)-alkyl, carboxyl, (Cl-C2)-alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (Cl-C2)-monoalkylamino, (cl-c2)-dialkyl~ino~
amino-(cl-c2)-alkyl~ (Cl-C2)-alkylamino-(Cl-C2)alkyl, di-(Cl-C2)-alkylamino-(Cl-C2)-alkyl, amidino, tri-fluoromethyl, (Cl-C~)-alkoxycarbonylamino, such as tert.butoxycarbonylamino, (C6-Cl2)-aryl-(cl_c2)_ alkoxycarbonylamino Euch as benzyloxycarbonylamino and methanesulfonylamino or trifluoromethane-sulfonylamino;

W stands for -C0-;

R2 denotes isobutyl, benzyl or cyclohexylmethyl;

R3 denotes hydrogen or hydroxyl;

R~ denotes a radical of the formula II, in which R5 stands for hydrogen or fluorine, D stands for a 2-, 3- or 4-pyridine radical, a 2-, 4- or S-imidazole radical or a 2-oxazoline radical, where the heterocycles mentioned can in each case be substituted by one or two radicals from the group comprising methyl, ethyl, propyl, allyl, fluorine, chlorine, bromine, CF3 and methoxy, and m denotes 0, 1 or 2; and 0 A and B independently of one another denote a bivalent radical from the series comprising phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspar-tic acid, ~-2-thienylalanine, ~-3-thienylalanine, ~-- 8 - 2 0 ~ ~ ~ 7 ~
2-furylalanine, ly~ine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenyl-alanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylala-nine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine,O-methyltyrosine,O-benzyltyrosine, O-tert.-butyltyrosine,phenylglycine,l-naphthylala-nine, 2-nsphthylalanine, 4-nitrophenylalanine, norvaline, norleucine, 1,2,3,4-tetrahydroisoquino-line-3-carboxylic acid, homophenylalanine, 2-amino-4-(2-thienyl)-butyric acid and 1-, 3- and 4-pyrazol-ylalanine, and their physiologically tolerable salts.

The invention furthermore relates to a process for the preparation of compounds of the formula I which comprises coupling a fragment having a terminal carboxyl group or its reactive derivative with a corresponding fragment having a free amino group, optionally removing (a) protective group(s) temporarily introduced for the protection of other functional groups and optionally converting the compound thus obtained into its physio-logically tolerable salt.

Fragments of 8 compound of the formula I having a ter-minal carboxyl group possess the formulae IIIa, IIIb or IIIc below:

Ra-W-OH Ra W-A OH Ra-W-~-~-OH

IIIa IIIb IIIc Fragments of a compound of the formula I having a ter-minal amino group possess the formulae IVa, IVb or IVc below:

9 20~7~

~2 ~ R3 H2N-A-B-NH-CH-CH-CH-R4 IVa ~2 ~R ~3 H2N-B-NH-CH-CH-CH-R4 IVb ~2 ~H ~3 H2N-CH-CH-CH-R4 IVc Methods which are suitable for the preparation of an S amide bond are describQd, for example, in Houben-Weyl, Methoden der organischen Chemie (Methods of Organic chemistry)~ volume 15/2; Bodanszky et al., Peptide syn-thesis, 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides. Analy is, synthesis, biology (Academic Press, New York 1979). The following methods are preferably useds active ester method using N-hydroxysuccinimide or 1-hydroxybenzotriazole a8 the ester component, coupling with a carbodiimide such ns dicyclohexylcarbodiimide or with propanephosphonic anhydride snd the mixed anhydrlde method with pivaloyl chloride.

The preparation of the optically active ~mines u~ed as starting compounds of the for ula IVc H2N-~H-CH- ~-R4 IVc in which R2, R3 and R~ are as defined above, is carried out starting from optically active ~-amino acids, the asymmetric center of which is retained. For this purpose, an N-protected amino acid aldehyde is prepared in a known manner, coupled in an aldol-analogous addition to a corresponding heteroarylalkyl building block and, after removing the N-protective group, gives amino alcohols of lo 2 0 ~
the formula IVc. Diastereomeric mixtures relative to the OH-carrying center are obtained which can be separated in a manner known per se, for example by fractional crystallization or by chromatography. The checking of the diastereomeric purity iE carried out by means of HPLC, and the enantiomeric purity can be checked in a known manner by converting into Mosher derivatives (H.S. Mosher et al., J. Org. Chem. 34, 2543 (1969)).

The preparation of N-protected amino acid aldehydes is carried out according to B. Castro et al. (Synthesis 1983, 676).

The aldol-analogou~ addition to N-protected amino acid aldehydes (preferably N-tert.-butoxycarbonyl and benzyl-oxycarbonyl protective groups) is carried out in a solvent inert towards bases, such as ether, THF, toluene, DMF, DMSO or dimethoxyethane.

Bases which can be used for the deprotonation of the heteroarylalkyl component are alkali metal alcoholates, such as potassium O-tert.-butylate, sodium methylate, alkali metal hydrides, such as sodium hydride or potas-sium hydride, organometallic bases, such as n-butyl-lithium, s-butylIithium, methyllithium or phenyllithium, sodium amide and alkali metal salts of organic nitrogen bases, such as lithium dii~opropylamide.

The preceding and subsequent operations necessary for the preparation of compounds of the formula I such as intro-duction and removal of protective groups are known from the literature and described, for example, in T.W.
Greene, "Protective Groups in Organic Synthesis n . Salts of compounds of the formula I with salt-forming groups are prepared in a manner known per se, for example by reacting a compound of the formula I having a basic group with a stoichiometric amount of a suit ble acid.

Mixtures of stereoisomers, in particular mixtures of 11- 20~7~
diastereomers, which are obtained using racemic amino acids A or B, can be separated by fractional crystallization or by chromatography in a manner known per se.

The compounds of the formula I according to the invention exhibit enzyme-inhibiting properties; in particular they inhibit the action of the natural enzyme renin. Renin is a proteolytic enzyme of the aspartylprotease class which, as a result of various stimuli (volume depletion, sodium deficiency, ~-receptor stimulation), iB secreted by the ~uxtaglomerular cells of the kidney into the blood circulation. In the latter it cleaves the decapeptide angiotensin I from the angiotensinogen liberated from the liver. Thi~ is converted into angiotensin II by the Nangiotensin converting enzyme~ (ACE). Angiotensin II
plays an essential role in the regulation of blood pr~e~sure, since it directly increases the blood pressure by means of vascular contraction. Additionally, it stimulates the secretion of aldosterone from the adrenal gland and in this manner increases the extracellular fluid volume via the inhibition of sodium excretion, which for its part contributes to an increase in blood pressure. Inhibitors of the enzymatic activity of renin cause a decreased formation of angiotensin I, which has a decreased formation of angiotensin II as a consequence.
The lowering of the concentration of this active peptide hormone is the direct cause of the hypotensive action of renin inhibitors.

The activity of renin inhibitors can be checked by in vitro tests. In this connection, the decrease in the formation of sngiotensin I is measured in various systems (human plasma, purified human renin).

1. Test principle Human plasma, for example, which contains both renin and angiotensinogen, is incubated at 37C with the compound - 12 - 2~
to be tested. In the course of this, angiotensin I iB
released from angiotensinogen under the action of renin and can subsequently be measured using a commercial radioimmunoassay. This angiotensin release is inhibited by renin inhibitors.

2. Obtaining the plas ~

The blood is obtained from volunteer sub~ects (about 0.5 1 per person; Bluko sampling device from ASID Bonz und Sohn, UnterschleiBheim) and collected in partially evacuated bottles with ice cooling. The clotting is prevented by adding EDTA (final concentration 10 mM).
After centrifuging (HS 4 rotor (sorvall)~ 3,500 rpm, O-4C, 15 min; repeat if necessary), the plasma iB care-fully pipetted off and frozen in suitable portions at -30C. Only plasmas having a sufficiently high renin activity are used for the test. Plasmas having low renin activity are activated by cold treatment (-4C, 3 days) (prorenin renin).

3. Carrying out the test Angiotensin I is determined using the renin Maia kit (Serono Diagnostics S.A., Coinsins, Switzerland). The incubation of the plasma is carried out accordinq to the instructions given theres Incubation batch: 1000 ~1 of plasma (thawed at 0-4-C) 100 ~1 of phosphate buffer (pH 7.4) (addition of 10-~ M
ramiprilate) 10 ~1 of PMSF solution 10 ~1 of 0.1 % Genapol PFIC
12 ~1 of DMSO or test preparation The test preparations are in general dissolved at 10 2 in 100 ~ dimethyl sulfoxide (DNSO) and diluted correspon-dingly with DMSO; the incubation batch contains a maximum - 13 - 201~7~
of 1 ~ DMS0.

The batches are mixed in ice and placed in a water bath (37C) ~or 1 hour for incubation. A total of 6 samples (in each case 100 ~1) are taken without further incuba-tion from an additional batch without inhibitor for the determination of the starting angiotensin I content of the plasma used.

The concentration of the test preparations are chosen 80 that approximately the range from 10-90 % enzyme inhibi-tion i8 covered (at least five concentrations). At the end of the incubation time, three 100 ~1 samples from each batch are frozen on dry ice in precooled Eppendorf vessels and stored at about -25C for the angiotensin I
determination (mean value of three individual samples).

Angiotensin I radioi~ unoassay (RIA) The instructions for use of the RIA kit (renin Maiae kit, Serono Diagnostics S.A., Coinsins, Switzerland) are followed exactly.

The calibration curve include6 the region from 0.2 to 25.0 ng of àngiotensin I per ml. The base angiotensin I
content of the plasma is taken away from all measured values. The plasma renin activity (PRA) is given as ng of Ang I/ml x hour. PRA values in the presence of the test substances are based on a batch without inhibitor (= 100 %) and given as % residual activity. The IC50 value is read off on the plot of ~ residual activity against the concentration (M) of the test preparation (logarith-mic scale).

The compounds of the general formula I described in the pre~ent invention show inhibitory actions at concentra-tions of about 10-5 to 10-1 mol/l in the in vitro test.

Renin inhibitors cause a lowering of blood pressure in - 14 - 2015~7~
salt-depleted animals. Since human renin differs from the - renin of other species, primates (marmosets, rhesus monkeys) are used for the in vivo test of renin inhibi-tors. Primates' renin and human renin are substantially homologous in their sequence. An endogenous effusion of renin is stimulated by i.v. in~ection of furosemide. The test compounds are then administered and their action on blood pressure and heart rate is measured. The compounds of the present invention are in this case active in a dose range from about 0.1 - 5 mg/kg i.v., and on intra-duodenal administration by ga~troscope in the dose range from about 1-50 mg/kg. The compound~ of the general formula I described in the present invention can be used as antihypertensives and also for the treatment of cardiac insufficiency.

The HIV protease is excised autocatalytically from the GAG-POL polypeptide and then cleaves the precursor peptide p55 in the core antigens pl7, p24 and pl4. It is thus an essential enzyme, whose inhibition interrupts the life cycle of the virus and suppresses its reprocation.

In biological tests, it has been shown that the compounds according to the invention have enzyme-inhibitory action and also inhibit viral enzymes such as HIV protease. The HIV protease-inhibiting action has a particular impor-tance, which qualifies the compounds according to theinvention in particular for the therapy and prophylaxis of disorders caused by infection with HIV. The compounds of the general formula I according to the invention show inhibitory actions at concentrations of about 10-~ to 10-~ mol/l in the in vitro tests used.

The invention furthermore relates to the use of compounds of the formula I for the preparation of medicaments for the therapy of high blood pressure and the treatment of congestive cardiac insufficiency and for the therapy and prophylaxis of viral disorders, in particular disorders which are caused by HIV, and also to the medicaments _ 15 - 2 ~1~ O l ~
mentioned.

Pharmaceutical preparations contain an effective amount of the active compound of the formula I together with an inorganic or organic pharmaceutically utilizable exci-pient. Administration can be carried out intranasally,intravenously, subcutaneously or perorally. The dosage of the active compounds depends on the warm-blooded animal species, the body weight, the age and the manner of administration.

The pharmaceutical preparations of the present invention are produced in dissolving, mixing, granulating or tablet-coating processes known per se.

For a form for oral administration, the active compounds are mixed with the additives customary therefor such as excipients, stabilizers or inert diluents and, by custo-mary methods, brought into suitable forms for administration, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium pho~phate, lactose, glucose, magnesium stearylfumarate or starch, in parti-cular maize starch. The preparation can be carried out both as dry and moist granules here. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil and cod liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts are brought into solutions, ~uspensions or emulsion~, if desired with the substances customary therefor such as solubilizers, emulsifiers or other auxiliaries. Possible solvents are, for example: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, or else a mixture of the - 16 - 20~507~
different ~olvents mentioned.

List of th~ abbreviations used:

ACC 4-aminocyclohexylcarbonyl Boc tert.-butoxycarbonyl BuLi n-butyllithium DCC dicyclohexylcarbodiimide DCI desorption chemical ionization DNP 2,4-dinitrophenyl DME dimethoxyethane DMF dimethylformamide EA ethyl acetate EI electron impact FAB fa~t atom bombardment h hour HOBt 1-hydroxybenzotriazole M molecular peak MS mass spectrum MTBE methyl tert.butyl ether NEM N-ethylmorpholine 20 n-PropPA n-propylphosphonic anhydride THF tetrahydrofuran The other abbreviations used for amino acid~ correspond to the three letter code customary in peptide chemistry as is described, for example, in Eur. J. Biochem. 138, 9-37 (1984). If not expressly stated otherwise, the amino acids are of the L-configuration.

The eluents used are abbreviated as followss Ell CH2Cl2/CH30H 20sl E12 CH2Cl2/CH30H 9sl E13 CH2Cl2/CH30H 12sl E14 CH2Cl2/CH30H/conc. NH3 10:1:0.1 E15 cyclohexane/ethyl acetate 9:1 E16 n-hexane/ethyl acetate 2:1 20~5~7~

The examples below serve to illustrate the present invention without limiting it thereto.

Fxn ple 1 N-(N-Tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-L-phenylalanine-L-norvaline-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide 98 mg of HOBt, 130 mg of DCC and 0.08 ml of NEM were added to 235 mg of N-(N-tert-butoxycarbonyl-cis-4-amino-cyclohexylcarbonyl)-L-phenylalanine diesolved in 3 ml of DMF. 230 mg of L-norvaline-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))-pentylamide, dissolved in 3 ml of DMF, were added to this solution and the mixture was stirred overnight at RT. The DMF was distilled off in a high vacuum, the solution remaininq was taken up in ethyl acetate, precipitated urea was filtered off and the filtrate was washed twice with satd. NaHCO3 and satd. NaCl solution, and the organic phase was dried over NgSO~ and concentrated in vacuo. 315 mg were isolated by column chromatography (silica gel, Ell).
Melting point 100-103-C
MS (FAB) 748 (M+l) a) N-(N-Tert-butoxycarbonyl-cis-4-aminocyclohexylcar-bonyl)-L-phenylalanine 5.5 g of N-(N-tert-butoxycarbonyl-cis-4-aminocyclohexyl-carbonyl) -L-phenylalanine benzyl ester were hydrogenated in 230 ml of ethanol over 1 g of Pd/carbon under normal pressure. After completion of the reaction, the cataly~t was filtered off and the solvent was removed by distilla-tion. 4.1 g of colorless product were obtained after recrystallization from n-heptane/ethyl acetate.
Melting point 160-161C (decomposition) MS (DCI) 391 (M+l) _ 18 - 201~07~
b) N-(N-Tert-butoxycarbonyl-cis-4-aminocyclohexylcar-bonyl)-L-phenylalanine benzyl ester 6.0 g of N-tert-butoxycarbonyl-cis-1,4-aminocyclohexane-carboxylic acid and 6.3 g of L-phenylalanine benzyl ester were dissolved in 75 ml of DMF and mixed with 24 ml of n-prop PA and 15.7 ml of NEM at 0C and the mixture was made to react overnight at RT. The solution was diluted with CH2C12 and washed in each case with semi~aturated NaHC03 solution, 10 ~ strength citric acid and water, dried over NgS0~ and concentrated in vacuo. Flash chroma-tography gave 5.7 g of pure prcduct.
: -14.6 (c = 1.1 in CH30H) B~a ple 2 N-(cis-4-Aminocyclohexylcarbonyl)-L-phenylalanine-L-norvaline-(1-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyri-dyl))-pentylamide 77.7 mg of the compound described in Example 1 were dissolved in 2 ml of CH2Clz and 2 ml of CF3COOH were added at 0C under N2. The solution was concentrated after 30 min, the residue was taken up in ethyl acetate and washed twice each time with satd. NaHC03 and NaCl solu-tion.
Column chromatography (silica gel, ~11) gave 24.7 mg of product.
NS (FAB) 648 (M+l) 19 -- 2 ~
X~ample 3 N-(N-Tert~butoxycarbonyl-~xans-4-aminocyclohexylcar-bonyl)-L-phenylalanine-L-norvaline-(l-S-cyclohexylmethyl-2-S-hydroxy-5-l2-pyridyl))pentylamide Analogously to thP process described in Example 1, the title compound was prepared from N-tN-tert-bu~oxycar-bonyl-trans-4-aminocyclohexylcarbonyl)-L-phenylalanine snd L-norvaline-~l-S-cyclQhexylmethyl-2-S-hydroxy 5-(2-pyridyl))pentylamide. The yield was 270 mg.
Melting point: 219-220~C.
M5 lFAB) 748 (M+1) a) N-(N-Tert-butoxycarbonyl-trans-4-aminocyclohexylcar bonyl)-L-phenylalanine 4.45 g of N-~N-tert-butoxycarbonyl-tran~-4-aminocyclo-hexylcarbonyl)-L-phenylalanine benzyl ester were cataly-tically hydrogenated under normal pressuxe over 900 mg of palladium-carbon in 200 ml of ethanol at RT. After completion of the reaction, the catalyst was filtered off and the solvent was removed by distillation in vacuo.
2.67 g of pure product were obtained after recrystallization.
Melting point: decomposition from 160C
MS (DCI): 391 (M+) b) N-(N-Tert-butoxycarbonyl-trans 4-aminocyclohexylcar-bonyl)-L-phenylalanine benzyl ester 3 g of N-tert-butoxycarbonyl-trans-4-aminocyclohexane-carboxylic acid and 3.2 g of L-phenylalanine benzyl e~ter were di~solYed in 40 ml of DMF and 7.85 ml of NEM and then 12 ml of n-propPA were added at 0C. The mixture was made to react overnight at RT. After diluting with 200 ml of ethyl acetate, the Eolution wa6 washed twice each with H2O, 10 % strength citri.c acid, satd. NaHCO3 and satd.
NaCl solution. The remaining organic phase was dried using MgSO4 and freed from the solvent in vacuo. ~he crude - 20 - 2 0 ~ ~ ~7 ~
product was triturated with diethyl ether, and the precipitated crystals were filtered off with suction and dried. 4.45 g of colorless crystals were obtained.
Melting point: 176-177-C
MS (DCI) 481 (M+l) ~a ple 4 N-(N-trans-4-Aminocyclohexylcarbonyl)-L-phenylalanine-L-norvaline-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyri-dyl))-pentylamide The title compound was prepared by the proces6 described in Example 2 from the compound de6cribed in Example 3.
Yield after chromatography (silica gel, E12) 27 mg.
MS (FAB) 648 (M+l) RF 0,17 (CH2C12/CH3OH 8:2) Exa ple 5 N-(N-Tert-butoxycarbonyl-tran~-4-aminocyclohexylcar-bonyl)-L-phenylalanine-N(im)-trityl-L-histidine-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound was prepared from the phenylalanine derivative described in Example 3a) and from FMOC-trityl-His-(1-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))-pentylamide by the process described in Example 1.
Yield after chromatography (silica gel, Ell) 0.4 g MS (PAB) 1028 (M+l), 1034 (M+7).
RF 0~5 (toluene/ethanol 8:2) Example 6 N-~N-Tert-butoxycarbonyl-trans-4-aminocyclohexylcar-bonyl)-L-phenylalanine-L-histidine-(1-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide 40 mg of the substance obtained in Example 5 were dis-solved in 5 ml of 90 % strength acetic acid and the mixture was heated to 60-C for two hours. The solution was ad~usted to pH 8 using Na2CO3 and extracted three times using ethyl acetate. The organic phase was washed twice each with satd. NaHCO3 solution and with satd. NaCl solution, then dried over MgSO~ and concentrated in vacuo.
Chromatography (silica gel, Ell) gave 16 mg of pure product. 155C decomposition MS (FAB) 786 (M+l) Esa ple 7 N-(trans-4-Aminocyclohexylcarbonyl)-L-phenylalanine-L-histidine-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyri-dyl))pentylamide 300 mg of the substance described in Example 5 were stirred for 15 min at O-C and for 2 h at RT with 5 ml of CF3COOH and 0.25 ml of H20. The solution was concentrated in vacuo, and the residue was rendered alkaline with NaHCO3 solution and extracted using ethyl acetate. The organic phase WaB concentrated in vacuo and the residue was chromatographed (~ilica gel, E12). Melting point 114-116C.
MS (FAB) 686 (M+l) ~x~ ple 8 N-(N-Tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-L-phenylalanine-N(im)-trityl-L-histidine-(l-S-cyclohexyl-methyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound was prepared from the phenylalanine . - 22 - 2~
derivative described in Example la) and from FMOC-trityl-His-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl)-- pentylamide by the process described in Example 1. Yield after chromatography (silica gel, Ell) 0.5 g.
MS (FAB) 1028 (M+l), 1034 (M+7) RF 0,26 (El 1) ~xa ple g N-(N-Tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-L-phenylalanine-L-histidine-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound was prepared by the process described in Example 6 from the compound described in Example 8.
MS (FAB) 786 (M~l) Yield: 61 mg. Melting point 127-130C. RF 0,21 (El 2) Es~mple 10 N-(cis-4-Aminocyclohexylcarbonyl)-L-phenylalanine-L-histidine-(1-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyri-dyl))pentylamide The title compound was prepared by the process described in Example 7 from the compound described in Example 8.
Yield 180 mg. Melting point 177C(decomp.) MS (FA~) 686 (M+l) Bs~ ple 11 N-(N-Tert-butoxycarbonyl-trans-4-aminocyclohexylcar-bonyl)-O-methyl-L-tyrosine-N-(im)-trityl-L-histidine-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound was prepared from N-(N-tert-butoxycar-bonyl-trans-4-aminocyclohexylcarbonyl)-methyl-L-tyrosine and trityl-L-His-(l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide by the process described in Example l. R 0,54 (toluene/ethanol 8:2) MS (~AB) 1058 (M+l) ~ 2~ _ 2~
~ampl~ 12 N-(N-Tert-butoxycarbonyl-trans~4-aminocyclohexylcar-bonyl)-0-methyl-L-tyrosine-L-histidine (l-S-cyclohexyl-methyl-2-S-hydroxy-5-(2-pyridyl))pen~ylamide The title compound was prepared by the process described in Example 6 from the compo~nd described in Example 11.
MS (FA~) 816 tM+l) 180C decomposition, RF 0~2 (toluene/
ethanol 8:2) Example 13 N-(trans-4-Aminocyclohexylcarbonyl)-0-methyl-L-tyrosine-L-histidine (l-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound was prepared by the process described in Example 7 from the compound de~cribed in Example 11.
MS (FAL) 716 ~M+l) E~ample 14 N-(N Tert-butoxycarbonyl-ci~-4-aminocyclohexylcarbonyl)-0-methyl-L-tyrosine-N-(im)-trityl-L-histidine (l-S-cyclo-hexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound Wa8 prepared from N-(N-tert-butoxycar-bonyl-cis-4-aminocyclohexylcarbonyl~-0-methyl-L-tyrosine and trityl-L-Hi~-(l-S-cyclohexyLmethyl-2~S-hydroxy-5-(2-pyridyl))pentylamide by the proces~ described in Example 1. RF 0,75 (El 2).
MS (FAB) 105~ (M~l) - 24 - 201507~
B~aple 15 N-(N-Tert-butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-O-methyl-L-tyrosine-L-histidine (1-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound wa8 prepared by the process described in Example 6 from the compound described in Example 14.
MS (FAB) 816 (N+l) RF 0,80 (El 4) ~ ple 16 N-(cis-4-Aminocyclohexylcarbonyl)-O-methyl-L-tyrosine-L-histidine (1-S-cyclohexylmethyl-2-S-hydroxy-5-(2-pyridyl))pentylamide The title compound was prepared by the process described in Example 7 from the compound described in Example 14.
MS (FAB) 716 (M+l) RF 0~50 (El 4) ~ pl~ 17 N-(N-(N-(eis-4-Tert.butoxycarbonyl~mino-cyclohexylcar-bonylphenylalaninyl)-h$~tidinyl)-2-(5-S-amino-6-cyclo-hexyl-3S,4R-dihydroxy-n-hexyl)-pyridine 60 mg of the compound from Example 17 a) are stirred with 40 mg of thiophenol in 2 ml of acetonitrile for 2 h.
After concentrating, the residue is chromatographed (silica gel, E14) and 45 mg are obtained as an amorphous powder.
MS (FAB) 802 (M+l) - 25 - 2 0 ~ ~ a ~ ~
a) Boc-cis-ACC-Phe-DNP-His-2-(5-amino-6-cyclohexyl-3S,4R-dihydroxy-n-hexyl)pyridine 60 mg of BOC-DNP-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxyhexyl)pyridine are stirred in 5 ml of DME/HCl for 2 h. After concentrating, the crude product is dissolved in 3 ml of DMF together with 50 mg of N-(N-tert.butoxycarbonyl-cis-4-aminocyclohexylcarbonyl)-L-phenylalanine, 120 mg of DCC and 80 mg of HOBt. The solution is ad~usted to pH 9 using NEM and stirred for 16 h. The solution is filtered, diluted with ethyl acetate and washed once each with 3 % strength NaHCO3 solution, H20 and satd. NaCl solution, dried using MgSO~, concentrated and chromatographed on silica gel (E13).
60 mg of the title compound are obtained as a yellow foam.
MS(FAB) 968 (N+l) b) BOC-DNP-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxyhexyl)pyridine 0.5 mmol of the (3S,4R,5S)isomer from Example 17 c are stirred with 5 ml of HC~ in DME (saturated) for 2 h.
After concentrating in vacuo, the re6idue is dissolved in 3 ml of absolute DMF. O.5 mmol each of BOC-DNP-His-OH, dicyclohexylcarbodiimide and HOBt are added. The solution is ad~usted to pH 9 using NEM and stirred for 24 h. After filtration, it is diluted with EA and washed with each 3 % strength NaKCO3 solution, dried using MgSO~ and concentrated. Chromatography on silica gel (Ell) gives the title compound a8 a yellow resin.
NS (FAB) 696 (N+l) c) 2-((3S,4R,5S)-5-tert.butoxycarbonylamino-3,4-di-hydroxy-6-cyclohexyl-n-hexyl)pyridine 1.4 ml (1 mmol) of n-BuLi are added at -78C to 93 mg (1 mmol) of 2-picoline in 10 ml of THF. After warming to RT, the mixture is stirred for 30 min, then cooled to - 26 - 2Q~
-40'C. 1 mmol of (2RS,3R,4S)-3-tert.-butyldimethylsilyl-oxy-4-tert.-butoxycarbonylamino-5-cyclohexyl-1,2-oxopen-- tane (known from EP-A 189,203, Example 6) are added (dissolved in 5 ml of THF). After 10 hours at RT, the mixture is diluted with water and extracted using MTBE.
The crude product (0.4 g) is dissolved in THF and stirred at 0-C with 5 ml of a lM solution of tetrabutylammonium fluoride in THF for 1 h. After diluting with water and extracting with EA, 0.15 q of the (3S,4R,5S)-isomer (MS
(FAB)s 391 (M+1) and 0.12 g of the (3S,4S,5S)-isomer (NS
(FAB): 391 (M+1) are obtained.
Fxample 18 cis-4-Aminocyclohexylcarbonyl-L-Phe-L-His-(1-S-cyclo-hexylmethyl-2R,3S-dihydroxy-5-(2-pyridyl))-n-pentylamide tristrifluoroacetate 25 mg of the compound described in Example 17 are stirred in 1 ml of TFA/1 ml of CH2Cl2 for 2 h. After concentrat-ing, the residue is taken up in H2O and lyophilized. 20 mg of product are obtained as a colorless powder.
MS (FAB) 702 (M+l) ~sa ple 19 BOC-trans-ACC-L-Phe-L-Hi~-(lS-cyclohexylmethyl-2R,3S-dihydroxy-5-(2-pyridyl))-n-pentylamide The title compound was prepared by the process described in Example 17 from the compound described in Example l9a.
MS (FAB) 802 (M+l)yield 79,5 mg. RF 0,19 (El 2) a) BOC-trans-ACC-L-Phe-L-DNP-His-(lS-cyclohexylmethyl-2R,3S-dihydroxy-5-(2-pyridyl))-n-pentylamide The title compound was prepared by the process described ~s~3'~;

in Example 17 a) from the compound~ de~cribed in Examples 3 a) and 19 b). RF 0~40 (El 2) MS ~FAB) g68 (M+1) b) DNP H-His-(3S,4R,5S)-2-(5-amino-6-cyclohexyl-3,4-dihydroxy-n-hexyl)-pyridine hydrochloride 400 mg of the compound from ~xampl2 17 b) are stirred in 10 ml of DME/HCl (satd.) for 2 h. Af~er concentrating, the residue is taken up in toluene twice and in each ca~e concentrated ayainr The title compound i8 obtained as a yellow foam.
MS (FAB) 596 (M+l) ~ample 20 trans-ACC-L-Phe-L-His-(lS-cyclohexylmethyl-2R,3S-di-hydroxy-5-(2-pyridyl))-n-pentylamide The title compound was prepared by the proces~ described in Example 18 from the compound de~cribed in Example 19.
MS (FAB) 702 (~+1) Yield: 49 mg ~ampl~ 21 BOC-trans-ACC'-O-methyl-L-Tyr-L-His-(lS-cyclohexylmethyl-2R,3S-dihydroxy-5-[2-pyridyl))-n-pentylamide The title compound was prepared by the proces~ described in Example 17 from the compound described in ~xample 21 a~.
MS (FAB) 832 ~M~l) 5 a) BOC trans-ACC-O-methyl-L-Tyr-DNP L-Hi~-(lS-cyclo-hexylmethyl-2R~3S dihydroxy-5-(2-pyridyl~)-n-pentyl-amide The title compound wae prepared by the proce~s de~cribed in Example 17 a) fro~ the compound~ de~cribed in ~xamples - 28 - 2 ~ ~ ~ S~ ~
21 b) and 19 b).
MS (FAB) 998 (M+l) b) BOC-trans-ACC-Tyr(OCH3)-OH

0.05 mol of BOC-trans-ACC-Tyr(OCH3)-OCH3 are dissolved in 250 ml of DNE and the mixture is stirred with an equi-molar amount of lN NaOH solution for 5 h. The solution is then concentrated and the residue is taken up with water, acidified to pH 4 using RHSO4 and extracted with EA. The crude product is recry~tallized from n-heptane/EA snd the title compound is obtained as a white powder.
NS (DCI) 421 (M+l) Melting point: 181C(decomp.) RF 0,20 (toluene/ethanol ~:2) c) BOC-trans-ACC-Tyr(OCH3)-OCH3 0.1 mol of BOC-trans-ACC-OH and 0.1 mol of L-tyrosine-(OCH3) methyl ester are dissolved in 500 ml of DNF and the mixture is stirred at O-C under N2 with 100 ml of n-propPA (50 % strength in CH2Cl2) and 0.5 mol of triethyl-amine. The solution is made to react overnight. After completion of the reaction (TLC checking)~ the solvent i8 removed by distillation in a high vacuum and the residue is taken up in EA. The organic phase is washed twice each with 10 % strength citric acid, water, semisaturated NaHCO3 solution and satd. NaCl solution, dried over NgSO~
and concentrated in vacuo, and the residue is chromatographed (silica gel, E15).
Melting point: 150-155 C.
MS (DCI) 435 (N+1) E~ ple 22 .

trans-ACC-O-methyl-L-Tyr-L-His-(lS-cyclohexylmethyl-2R,3S-dihydroxy-5-(2-pyridyl))-n-pentylamide The title compound was prepared by the process described in Example 18 from the compound described in Example 21.
MS (FAB) 732 (M+1) 20~ ~Q7~
2g Bxa ple 23 Boc-cis-Acc-o-methyl-L-Tyr-L-His-(ls-cyclohexylmeth 2R,3S-dihydroxy-5-(2-pyridyl))-n-pentylamide The title compound was prepared by the proce~s described in Example 17 from the compound described in Example 23 a). RF 0,21 (El 2) MS (FAB) 832 (M+1) a) BOC-cis-ACC-O-methyl-L-Tyr-DNP-L-His-(lS-cyclo-hexylmethyl-2R,3S-dihydroxy-5-(2-pyridyl))-n-pentyl-amide The title compound was prepared by the process describedin Example 17 a) from the compounds described in Examples 23 b) and 19 b).
MS (FAB) 998 (M+l) b) BOC-cis-ACC-Tyr(OCH3)-OH

The title compound is obtained analogously to the process Example 21 b). d25= + 18,6 (c=1, CH30H) MS (DCI) 421 (M+l) c) BOC-cis-ACC-Tyr(OCH3) methyl ester The title compound was prepared analogously to the process in Example 21 c).
MS (DCI) 435 (M+l) ~x~ ple 24 cis-ACC-O-mothyl-L-Tyr-L-Hi~-(lS-cyclohexylmethyl-2R,3S-2S dihydroxy-5-(2-pyridyl))-n-pentylamide The title compound was prepared by the process described in Example 18 from the compound described in Example 23.

~ 30 - 20~7~
MS (FA~) ~32 (M+1) RF 0,56 (El 4) ~xa ple 25 BOC-cis-ACC-Phe-His-(lS-cyclohexylmethyl-2S-hydroxy-5-(N-propyl-2-imidazolyl))pentylamide The title compound was prepared by the process described in Example 17 from the compound described in Example 25.
MS (FAB) 817 (M+l) a) BOC-cis-ACC-Phe-DNP-His-(lS-cyclohexylmethyl-2S-hydroxy-5-(N-propyl-2-imidazolyl))pentylamide 80 mg of the compound from Example b are stirred with 4 ml of HCl in DME (satd.) for 2 h. After concentrating in vacuo, the residue is dissolved in 3 ml of absolute DMF. 44 mg of BOC-cis-ACC-Phe-OH and 0.11 mmol each of DCC and HOBt are added. The solution is ad~usted to pH 9 using NEN snd ~tirred for 24 h. After filtering, it i~
diluted with EA and washed twice each with 3 % strength NaHCO3 solution, H20 and satd. NaCl solution, dried using MgSO~ and concentrated. Chromatography on silica gel gives the title compound as a yellow resin.
MS (FAB) 9B3 (M+l) b~ BOC-DNP-His-(lS-cyclohexylmethyl-2S-hydroxy-5-(N-propyl-2-imidazolyl))pentylamide 100 mg of the compound from Example c are stirred with 5 ml of HCl in DNE (satd.) for 2 h. After concentrating in vacuo, the residue is dissolved in 3 ml of absolute DMF. 105 mg o$ BOC-DNP-His-OH and O.3 mmol each of DCC
and HOBt are added. The solution i8 ad~usted to pH 9 using NEM and ~tirred for 24 h. After filtration, it is diluted with EA and washed twice each with 3 % strength NaHCO3 solution, H20 and satd. NaCl solution, dried using MgSO~ and concentrated. Chromatography on silica gel gives the title compound as a yellow resin.

- 31 - 2~ ~ ~ 07 ~
MS (FAB) 711 (M+l) c) 3-BOC-4S-cyclohexylmethyl-2,2-dimethyl-5-(3-(2-N-propylimidazolyl)-propyl)oxazolidine 500 mg of the compound from Example d are dissolved in 5 ml of absolute THF. Under an argon atmosphere, 1.9 ml of a 1.5 molar solution of n-butyllithium in n-hexane are added at -60-C. After 15 min, 500 mg of the compound from Example e dissolved in 5 ml of absolute rn~ are added.
After 1 h at ~60C, 10 ml of a satd. NaHCO3 solution are added. After warming to RT, the mixture iB extracted three times with EA, dried using Na2SO4 and concentrated.
The title compound is obtained by chromatography on silica gel (El EA).
R(f) 0.3 (EA); MS (PAB) M+l) d) 2-Methyl-N-n-propylimidazole 10 g of 2-methylimidazole are heated to boiling in 40 ml of n-propylbromide for 2 h. The solution i8 then poured into 150 ml of a 5 % strength NaHSO~ solution, and the mixture is extracted three times using EA, dried using Na2SO4 and concentrated. The residue i8 taken up in ether and separated from insoluble starting material by filtra-tion. In this manner, the title compound is obtained as a colorless oil.
R(f) 0.2 (EA/CH30H lOsl) e) 3-Boc-cyclohexylmethyl-2,2-dimethyl-5-(2-bromo-ethyl)oxazolidine 1.6 ml of diathyl azodicsrboxylate are added dropwise at 20-C under argon to 690 mg of 3-BOC-lS-cyclohexylmethyl-2,2-dimethyl-5-(2-hydroxyethyl)oxazolidine, 2.6 g of triphenylphosphine and 1.6 g of pyridinium bromide in 15 ml of CH2Cl2. After 16 h at RT, water is added and the mixture i8 diluted using 100 ml of CH2C12. The organic phase is washed twice with satd. NaHCO3 solution and once 20~507~

with NaCl solution. The organic phase dried with Na2SO4 i~
concentrated, and the residue is taken up in a little EA
and filtered to separate PPh3. Purification on silica gel yields the title compound (E16).
R~f) 0.3 (E16); NS 404 (M+l).

f) 3-BOC-4S-cyclohexylmethyl-2,2-dimethyl-5-(2-hydroxy-ethyl~oxazolidine 10 g of BOC-ACHPA-OC2H5 (preparation according to J. Ned.
Chem. 28, 1779 (1985)), 500 mg of p-toluenesulfonic acid and 7.2 ml of dimethoxypropane are heated at 80-C in 160 ml of toluene under argon for 2 h. The mixture i8 then concentrated. The residue i~ added dropwise at 0-C
to a suspension of 2 g of LiAlH4 in 200 ml of THF. After 2.5 h at 0-C, 100 ml of 5 ~ strength NaHSO~ solution are added and the mixture is extracted three times with EA.
The combined organic phases are washed with satd. NaHCO3 solution. After drying using Na2SO~, the mixture is concentrated and chromatographed on silica gel (E16).
R(f) 0.1 (E16); MS (DCI) 342 (M+l).

E~ample 26 cis-ACC-Phe-His-(lS-cyclohexylmethyl-2S-hydroxy-5-(N-propyl-2-imidazolyl))pentylamide The title compound was prepared by the method de~cribed in Example 18 from the compound in Example 25.
NS (FAB) 717 (N+l)

Claims (8)

1. A compound of the formula I

(I) in which Ra denotes (C3-C8)-cycloalkyl, (C4-C10)-bicycloalkyl, (C8-C12)-tricycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C4-C10)-bicycloalkyl-(C1-C6-alkyl and (C6-C12)-tricycloalkyl-(C1-C6)-alkyl, in which in each case the cycloalkyl, bicycloalkyl and tricycloalkyl substituents can be substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyll (C1-C6)-alkoxy, (C1-C6)-alkyl, carboxyl, (C1-C6)-alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (C1-C6)-monoalkyl-amino, (C1-C6)-dialkylamino, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)alkyl, di-(C1-C6)-alkylamino-(Cl-C6)-alkyl, amidino, hydroxamino, hydroximino, hydrazono, imino, guanidino, (C1-C6)-alkyloxy-sulfonyl, (C1-C6)-alkyloxysulfenyl, trifluoromethyl, (C1-C4)-alkoxycarbonylamino or (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino;

W stands for -CO-, -O-CO- or -SO2-, R2 denotes hydrogen, (C1-C10)-alkyl, (C4-C7)-cycloalkyl, (C4-C7)-cycloalkyl-(C1-C4)-alkyl, (C6-C14)-ary1 or (C6-C14)-aryl-(C1-C4)alkyl, R3 denotes hydrogen, (C1-C10)-alkyl, (C8-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, hydroxyl or amino, R4 denotes a radical of the formula II

(CH2)m-CHR5-D (II) - 34 _ where R5 stands for hydrogen, (C1-C7)-alkyl, (C1-C5)-alkoxy, (C1-C5)-alkylthio, (C1-C5)-alkylamino, hydroxyl, azido, fluorine, chlorine, bromine or iodine, D denotes a radical Het, where Het denotes a 5- to 7-membered heterocyclic ring which can be fused to benzene, aromatic, partially hydrogenated or completely hydro-genated, which can contain one or two identical or different radicals from the group N, O, S, NO, SO or SO2 as heteroatoms and which can be substituted by one or two identical or dif-ferent radicals from the group comprising (C1-C4)-alkyl,(C1-C4)-alkoxy,hydroxyl,halogen, amino, mono- or di-(C1-C4)-alkylamino or CF3, and m denotes 0, 1, 2, 3 or 4;

A and B independently of one another denote an amino acid linked at the nitrogen terminus to Ra-W or A and at the carbon terminus to B or NH-CHR2-CHOH-CHR3-R4 from the series comprising phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, iso-leucine, asparagine, aspartic acid, .beta.-2-thienylala-nine, .beta.-3-thienylalanine, .beta.-2-furylalanine, p-3-furylalanine, lysine, ornithine, valine, alanine,

2,4-diaminobutyric acid, arginine, 4-chlorophenyl-alanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexyl-alanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-tert,-butyl-tyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, .beta.-2-benzo[b]thienylalanine, .beta.-3-benzotb]thienyl-alanine, 2-fluorophenylalanine, 3-fluorophenyl-alanine, 4-fluorophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroiso-quinoline-3-carboxylic acid, homophenylalanine, DOPA, O-dimethyl-DOPA, N-methylhistidine, 2-amino-4-(2-thienyl)-butyric acid, 2-amino-4-(3-thienyl)-butyric acid, 3-(2-thienyl)-serine, (Z)-dehydro-phenylalanine, (E)-dehydrophenylalanine, 1,3-dioxo-lan-2-ylalanine, N-pyrrolylalanine and 1-, 3- or 4-pyrazolylalanine, and their physiologically tolerable salts.

2. A compound as claimed in claim 1, wherein Ra and W
are as defined in claim 1, R2 denotes hydrogen, (C1-C10)-alkyl, (C4-C7)-cycloalkyl, (C4-C7)-cycloalkyl-(C1-C4)-alkyl, (C6-C14)-aryl or (C6-C14)-aryl-(C1-C4)alkyl, R3 denotes hydrogen, (C1C10)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, hydroxyl or amino, R4 denotes a radical of the formula II, in which R5 stands for hydrogen, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, hydroxyl, azido, fluorine, chlorine, bromine or iodine, D is defined as the radical Het in claim 1 and m denotes 0, 1 or 2;

A and B independantly of one another denote a bivalent radical from the series comprising phenylalanine, histidine, tyrosine, tryptophan, methionine, leucin-e, isoleucine, asparagine, aspartic acid, .beta.-2-thienylalanine, .beta.-3-thienylalanine, .beta.-2-furylalan-ine, .beta.-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 4-pyridylalanine, 3-pyridylalanine,cyclohexylalanine,cyclohexylglycin-e, im-methylhistidine, O-methyltyrosine, O-benzyl-tyrosine, O-tert.-butyltyrosiner phenylglycine, 1-naphthylalanine,2-naphthylalanine,4-nitrophenylal-anine, norvaline, .beta.-2-benzo[b]thienylalanine, .beta.-3-benzotb]thienylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, nor-leucine, cysteine, S-methylcysteine, 1,2,3,4-tetrah-ydroisoquinoline-3-carboxylicacid,homophenylalani-ne, DOPA, O-dimethyl-DOPA, N-methylhistidine, 2-amino-4-(2-thienyl)-butyric acid, 2-amino-4-(3-thienyl)-butyric acid, 3-(2-thienyl)-serine, (Z)-dehydrophenylalanine,(E)-dehydrophenylalanine,1,3-dioxolan-2-ylalanine, N-pyrrolylalanine and 1-, 3-or 4-pyrazolylalanine, and their physiologically tolerable salts.

3. A compound as claimed in claim 1 and/or 2, wherein Ra denotes (C4-C6)-cycloalkyl and (C4-C6)-cycloalkyl-(C1-C2)-alkyl, in which in each case the cyclo-alkyl substituent can be substituted by one or two identical or different radicals from the series comprising hydroxyl, (C1-C4)-alkoxy, (C1-C2)-alkyl, carboxyl, (C1-C2)-alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (Cl-C2)-mono-alkylamino, (C1-C2)-dialkylamino, amino-(C1-C2)-alkyl, (C1-C2)-alkylamino-(C1-C2)alkyl, di-(C1-C2)-alkylamino-(C1-C2)-alkyl, amidino, trifluoro-methyl, (C1-C4)-alkoxycarbonylamino such as tert.butoxycarbonylamino, (C6-C12)-aryl-(C1-C2)-alkoxycarbonylamino such as benzyloxycarbonyl-amino and methanesulfonylamino or trifluoro-methanesulfonylamino;

W stands for -CO-;

R2 denotes isobutyl, benzyl or cyclohexylmethyl;

R3 denotes hydrogen or hydroxyl;

R4 denotes a radical of the formula II, in which R5 stands for hydrogen or fluorine, D stands for a 2- or 4-pyridine radical, a 2-, 4- or 5-imidazole radical or a 2-oxazoline radical, where the heterocycles mentioned can in each case be substituted by one or two radicals from the group comprising methyl, methoxy, ethyl, propyl, allyl, fluorine, chlor-ine, bromine and CF3, and m denotes 0, 1 or 2; and A and B independently of one another denote a bivalent radical from the series comprising phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspar-tic acid, .beta.-2-thienylalanine, .beta.-3-thienylalanine, .beta.-2-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenyl-alanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylala-nine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine,O-methyltyrosine, O-benzyltyrosine, 0-tert.-butyltyrosine,phenylglycine,1-naphthylala-nine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, norleucine, 1,2,3,4-tetrahydroisoquino-line-3-carboxylic acid, homophenylalanine, 2-amino-

4-(2-thienyl)-butyric acid and 1-, 3- and 4-pyrazol-ylalanine, and their physiologically tolerable salts.

4. A process for the preparation of a compound of the formula I as claimed in one or more of claims 1 to 3, which comprises coupling a fragment having a terminal carboxyl group or its reactive derivative with a corres-ponding fragment having a free amino group, optionally removing (a) protective group(s) temporarily introduced for the protection of other functional groups and option-ally converting the compound thus obtained into its physiologically tolerable salts.

5. A compound of the formula I as claimed in one or more of claims 1 to 3 for use as a medicament.

6. A compound of the formula I as claimed in one or more of claims 1 to 3 for use as a medicament in the treatment of high blood pressure.

7. A pharmaceutical preparation containing a compound of the formula I as claimed in one or more of claims 1 to 3.

8. The dipeptide derivatives of the formula I as claimed in claim 1, and substantially as described herein.