DE3924506A1 - New poly:hydroxy:amide derivs. - Google Patents

Abstract

Peptide polyhydroxyalkylamides of formula (I) and their salts are new; where A = R1R6N-CHR5-CO-, R1R7CH-CHR5-CO- or R1O-CHR5-CO-; R1 = R'1 or R'1W; R'1 = (a) 3-8C cycloalkyl, CONH2, OCH2COOH, NH2, etc. (b) H, OH or 1-4C alkoxy, (c) 1-18C alkyl, quanidino, phenyl(1-4C)alkoxy, etc. (d) 6-14C aryl, (6-14C)aryl(1-4C)alkyl, etc. (e) Het or Het(1-4C)alkyl, where Het is an opt. benzo-fused 5- to 7-membered heterocyclic ring contg. 1 or 2 of N, O, S, No, etc. (f) NR8R9; Het or Het(1-4C)alkyl, or NR8R9 is a mono- or bicyclic 5- to 12-membered ring system opt. contg. 1 or 2 more N atoms, an S atom or an O atom, opt. substd. by 1-4C alkyl; W = CO, CS, OSO, SO2, SO, NHSO2, NHCO, CHOH or NOH; n = 2-10.

Description

From the European patent applications EP-A 1 84 855, 1 89 203, 2 02 571, 2 29 667, 2 30 266 and 2 37 202 and the International Patent Application WO 87/05302 discloses aminodiol Derivatives with reninhemmender effect known.

Furthermore, renin-inhibiting aminodiol derivatives are in Biochem. Biophys. Res. Commun. 132, 155-161 (1985), in Biochem. Biophys. Res. Commun. 146, 959-963 (1987), in FEBS Lett. 230, 38-42 (1988) and J. Med. Chem. 30, 976-982 (1987).

Surprisingly, it has now been found that such Compounds different from those mentioned in the documents described differ in that they are at the C-terminus contain additional hydroxy functions, highly effective Renin inhibitors are in vitro and in vivo and compared to the known compounds advantageous properties respectively.

The invention relates to compounds of the formula I.

in which
A is a radical of the formulas II, III or IV

R¹ is a₁) (C₃-C₈) -cycloalkyl, (C₄-C₁₀) -bicycloalkyl, (C₈-C₁₂) -tricycloalkyl, (C₃-C₈) -cycloalkyl- (C₁-C₆) -alkyl, (C₄-C₁₀) -bicycloalkyl (C₁-C₆) -alkyl, (C₈-C₁₂) -tricycloalkyl- (C₁-C₆) -alkyl, (C₃-C₈) -cycloalkylcarbonyl and (C₃-C₈) -cycloalkylsulfonyl, in which in each case the cycloalkyl-, bicycloalkyl- and Tricycloalkyl substituent by one or two identical or different radicals selected from F, Cl, Br, I, hydroxy, (C₁-C₆) alkoxy, (C₁-C₆) alkyl, carboxy, (C₁-C₆) alkoxycarbonyl , Carbamoyl, carboxymethoxy, amino, (C₁-C₆) monoalkylamino, (C₁-C₆) dialkylamino, amino (C₁-C₆) alkyl, (C₁-C₆) alkylamino (C₁-C₆) alkyl, di (C₁-C₆) -alkylamino (C₁-C₆) -alkyl, amidino, hydroxyamino, hydroximino, hydrazono, imino, guanidino, (C₁-C₆) -alkyloxysulfonyl, (C₁-C₆) -alkyloxysulfenyl, trifluoromethyl, (C₁-C₆) -alkyl C₄) alkoxycarbonylamino, (C₆-C₁₂) -aryl (C₁-C₄) alkoxycarbonylamino, may be substituted ;
Hydrogen, (C₁-C₁₈) alkyl, (C₁-C₁₈) alkanoyl, (C₁-C₁₈) alkoxycarbonyl, (C₁-C₁₈) alkylsulfonyl, (C₁-C₁₈) alkylsulfinyl, wherein the alkyl groups are each protected by optionally protected amino , Trimethylsilyl, hydroxy, mercapto, (C₁-C₄) -alkylthio, halogen, (C₁-C₄) -alkoxy, mono- or di- (C₁-C₈) -alkylamino, carboxy, carbamoyl, guanidino, (C₁-C₄) - Alkoxycarbonyl, (C₁-C₈) alkanoyloxy, phenyl (C₁-C₄) alkoxy or a radical CONR⁸R⁹ may be substituted; (C₁-C₄) alkoxy;
(C₆-C₁₄) aryl, (C₆-C₁₄) aryl- (C₁-C₄) alkyl, (C₆-C₁₄) aryl- (C₁-C₄) alkoxy, wherein the aryl radical in each case by one, two or three Radicals of the group (C₁-C₆) alkyl, amino, mono- or di- (C₁-C₄) alkylamino, amino (C₁-C₄) alkyl, hydroxy (C₁-C₄) alkyl, mono- or di - (C₁-C₄) -alkylamino- (C₁-C₄) alkyl, hydroxy, (C₁-C₄) alkoxy, halogen, formyl, (C₁-C₄) alkoxycarbonyl, carboxamido, mono- or di- (C₁-C₄ ) -alkylaminocarbonyl or nitro;
Het, Het- (C₁-C₄) alkyl, wherein Het represents a 5-, 6- or 7-membered heterocyclic ring which may be benzo-nated and either aromatic, partially hydrogenated or fully hydrogenated and the hetero element one or two radicals of the group N, O, S, NO, SO or SO₂ and by one or two radicals of the group (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) alkoxycarbonyl, hydroxy, halogen, amino, Mono- or di- (C₁-C₄) alkylamino may be substituted or a radical NR⁸R⁹ means, wherein
R⁸ and R⁹ are the same or different and are independently hydrogen; (C₁-C₈) alkyl which may be substituted by amino, (C₁-C₄) alkylamino, di- (C₁-C₄) alkylamino, hydroxy or (C₁-C₄) alkoxy, (C₃-C₇) cycloalkyl ; mercapto; (C₁-C₄) - alkylthio; phenylthio; (C₁-C₄) alkoxycarbonyl; Carboxy, (C₆-C₁₄) -aryl which may be substituted in the aryl radical as described above; Het or het (C₁-C₄) alkyl, wherein Het is as defined above, means or wherein
R⁸ and R⁹ together with the nitrogen atom they carry form a 5- to 12-membered ring which may be mono- or bicyclic and contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and by (C₁-C₄) - Alkyl may be substituted, or form
R¹ a₂) represents a radical of the formula V.

R ^{1 '} -W (V)

wherein R ^{1 'is defined} as R¹ under a₁) and W is -CO-, -CS-, -O-CO-, -SO₂-, -SO-, -NH-SO₂-, -NH-CO-, -CH (OH) - or -N (OH) - stands;
R² and R⁶ independently of one another denote hydrogen or (C₁-C₄) -alkyl,
R³ and R⁵ are independently defined as R¹ under a₁);
R⁴ is (C₃-C₁₂) -alkyl; mono-, bi- or tricyclic (C₃-C₁₈) -cycloalkyl, (C₃-C₁₈) -cycloalkylmethyl, (C₃-C₁₈) -cycloalkylethyl, wherein the cycloalkyl moiety is optionally substituted by (C₁-C₆) -alkyl; dithiolanyl; (C₆-C₁₄) arylmethyl; Dithiolanylmethyl; Dithiolanylethyl; dithianyl; Dithianylmethyl or dithianylethyl;
R⁷ is hydrogen or (C₁-C₈) -alkyl, or together with R¹ or R⁵ and the atoms carrying them forms a mono- or bicyclic, saturated or partially unsaturated ring system having 5-12 ring members, which may contain 1 sulfur atom in addition to carbon, which may optionally be oxidized to the sulfoxide or sulfone; and
n 2-10 means
and their physiologically acceptable salts.

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

Alkyl can be straight-chain or branched. The same applies to residues derived therefrom.

Under (C 6 -C 6) -cycloalkyl are cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl Roger that.

Under (C₄-C₁₀) bicycloalkyl or (C₈-C₁₂) -tricycloalkyl one understands an isocyclic aliphatic, not aromatic radical, which may be unsymmetrical may contain distributed double bonds, if appropriate also with open-chain aliphatic side chains may be substituted. The two or three rings as Components of such a radical are condensed or spiro-linked and via a ring C atom or a Linked side-chain C atom. Examples of these radicals are bornyl, norbornyl, pinanyl, norpinanyl, caranyl, Norcaranyl, thiocyanyl, adamantyl, bicyclo (3.3.0) octyl, Bicyclo (1.1.0) butyl, spiro (3.3) heptyl substituents.

If said cycles more than one substituent wear, so these can be both cis and trans to each other stand.

(C₆-C₁₄) -aryl is, for example, phenyl, naphthyl, Biphenylyl or fluorenyl; preferred is phenyl. The same applies to radicals derived therefrom, such as. B. Aryloxy, aroyl, aralkyl and aralkyloxy. Under aralkyl one understands one linked with (C₁-C₆) alkyl unsubstituted or substituted (C₆-C₁₄) aryl radical, such as B. benzyl, α- and β-naphthylmethyl, halobenzyl and Alkoxybenzyl, but aralkyl is not limited to those mentioned Remains would be limited.

A remainder Het in the sense of the above definition is for example, pyrrolyl, furyl, thienyl, imidazolyl,  Pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, Pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, β-carbolinyl or a benzannellated, cyclopenta, cyclohexa or cyclohepta-fused derivative of this Residues. This heterocycle can be attached to a nitrogen atom by oxido, (C₁-C₆) alkyl, z. Methyl or ethyl, phenyl or phenyl (C₁-C₄) alkyl, e.g. Benzyl, and / or on one or more carbon atoms by (C₁-C₄) alkyl, z. B. Methyl, phenyl, phenyl (C₁-C₄) alkyl, e.g. Benzyl, halogen, z. As chlorine, hydroxy, (C₁-C₄) alkoxy, z. Methoxy, Phenyl (C₁-C₄) alkoxy, e.g. B. benzyloxy, or oxo is substituted and partially saturated and is for example 2- or 3-pyrrolyl, phenyl-pyrrolyl, z. B. 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, Methyl imidazolyl, e.g. 1-methyl-2-, 4- or 5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl, 1-oxido-2-, 3- or 4-pyridyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or 5-indolyl, substituted 2-indolyl, e.g. B. 1-methyl, 5-methyl, 5-methoxy, 5-benzyloxy, 5-chloro or 4,5-dimethyl-2-indolyl, 1-benzyl-2 or 3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta [b] -5-pyrrolyl, 2-, 3- or 4-quinolyl, 4-hydroxy-2-quinolyl, 1-, 3- or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzoxazolyl, 2-Benzothiazolyl, benz [e] indol-2-yl or β-carbolin-3-yl.

Partially hydrogenated or fully hydrogenated heterocyclic Rings are, for example, dihydropyridinyl, pyrrolidinyl, z. B. 2-, 3- or 4-N-methylpyrrolidinyl, piperidinyl, Piperazinyl, morpholino, thiomorpholino.

Among salts of compounds of formula I are in particular pharmaceutically acceptable or non-toxic To understand salts.

Such salts are exemplified by compounds of the Formula I, which acidic groups, eg. Carboxy,  formed with alkali or alkaline earth metals, such as Na, K, Mg and Ca, as well as with physiologically acceptable organic Amines, such as. For example, triethylamine and Tri- (2-hydroxy-ethyl) -amine.

Compounds of formula I, which basic groups, for. B. an amino group or a guanidino group, form salts with inorganic acids, such as. Hydrochloric acid, Sulfuric acid or phosphoric acid and with organic Carboxylic or sulfonic acids, such as. Acetic acid, Citric acid, benzoic acid, maleic acid, fumaric acid, Tartaric acid and p-toluenesulfonic acid.

Preference is given to compounds of the formula I in which
A as defined on page 1;
R¹ is hydrogen or (C₁-C₁₀) -alkyl; cyclopentyl; cyclohexyl; Cyclopentyl (C₁-C₆) alkyl; Cyclohexyl (C₁-C₆) alkyl; Phenyl (C₁-C₄) alkyl, wherein the phenyl radical is optionally substituted as indicated on page 2; Thienyl or thienyl (C₁-C₄) alkyl, wherein the thiophene may each be substituted by one or two radicals of the group (C₁-C₄) alkyl, (C₁-C₄) alkoxy or halogen, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl (C₁-C₄) alkyl, wherein the pyridine radical is substituted by one or two radicals of the group (C₁-C₄) alkyl, (C₁-C₄) alkoxy or halogen can be means; H₂N- (C₁-C₁₀) alkyl; HO- (C₁-C₁₀) alkyl; (C₁-C₄) alkoxy (C₁-C₁₀) alkyl; (C₁-C₄) alkoxycarbonyl (C₁-C₁₀) alkyl; (C₁-C₈) -alkylsulfonyl; (C₁-C₈) -alkylsulfinyl; (C₁-C₈) -Hydroxyalkylsulfonyl; (C₁-C₈) -hydroxy-alkylsulfinyl; Hydroxy (C₁-C₁₀) alkanoyl; (C₁-C₈) alkanoyloxy (C₁-C₁₀) alkyl; (C₁-C₁₁) -alkanoyl; optionally protected amino (C₁-C₁₁) alkanoyl, such as (3-amino-3,3-dimethyl) propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert-butoxycarbonylaminobutyryl, 5- N-tert-butoxycarbonylaminopentanoyl or 6-N-tert-butoxycarbonylaminohexanoyl; Di (C₁-C₇) alkylamino (C₂-C₁₁) alkanoyl; (C₃-C₈) -cycloalkylcarbonyl; amino-substituted (C₃-C₈) -cycloalkyl-carbonyl; amino-substituted (C₃-C₈) -cycloalkyl-sulfonyl, (C₆-C₁₀) -aryl (C₂-C₁₁) -alkanoyl; 2-pyridyl (C₁-C₈) alkanoyl; 3-pyridyl (C₁-C₈) alkanoyl; 4-pyridyl (C₁-C₈) alkanoyl; optionally substituted by halogen, (C₁-C₆) alkyl, (C₁-C₄) alkoxy or (C₁-C₄) alkoxycarbonyl substituted benzoyl; benzenesulfonyl; (C₁-C₁₀) -alkoxycarbonyl, substituted (C₁-C₁₀) -alkoxycarbonyl; or (C₆-C₁₄) aryl- (C₁-C₆) alkoxycarbonyl;
R² and R⁶ independently of one another denote hydrogen or (C₁-C₄) -alkyl,
R³ and R⁵ are independently defined as R¹ a₁) on page 2;
R⁴ is (C₃-C₁₂) -alkyl; mono-, bi- or tricylic (C₃-C₁₈) -cycloalkyl or (C₃-C₁₈) -cycloalkylmethyl, wherein the cycloalkyl moiety is optionally substituted by (C₁-C₄) -alkyl; (C₆-C₁₄) arylmethyl; dithiolanyl; Dithiolanylmethyl; Dithianyl and dithianylmethyl;
R⁷ is hydrogen or methyl, or together with R¹ or R⁵ and these supporting atoms, a mono- or bicyclic saturated or partially unsaturated ring system having 5-12 ring members, which may contain 1 carbon atom in addition to carbon, which may optionally be oxidized to sulfoxide or sulfone , forms; and
n 2-8, means.

Particular preference is given to compounds of the formula I in which
R¹ is (C₁-C₈) alkylsulfonyl; (C₁-C₈) -alkylsulfinyl; 2-hydroxyethylsulfonyl; 2-hydroxy-propylsulfonyl; 2-hydroxypropionyl; 3-hydroxypropionyl; 3-hydroxybutyryl; 2-hydroxy-3-methylbutyryl; (C₁-C₈) alkanoyloxy (C₁-C₁₀) alkyl; n-decanoyl; formyl; Acetyl, propionyl; pivaloyl; isovaleryl; isobutyryl; (3-amino-3,3-dimethyl) -propionyl); 4-aminobutyryl; 5-aminopentanoyl; 6-aminohexanoyl; dimethylaminoacetyl; Piperidino-4-carbonyl; Morphonlino-4-carbonyl; cyclopropylcarbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl; cyclohexylcarbonyl; 3-Aminocyclobutylcarbonyl; 4-aminocyclohexylcarbonyl; 3-Aminocyclobutylsulfonyl; 4-Aminocyclohexylsulfonyl; phenylacetyl; phenylpropanoyl; phenylbutanoyl; 2-pyridyl (C₁-C₈) alkanoyl; 3-pyridyl (C₁-C₈) alkanoyl; 4-pyridyl (C₁-C₈) alkanoyl; 4-chlorobenzoyl; 4-methylbenzoyl; 2-methoxycarbonylbenzoyl; 4-methoxybenzoyl; Pyrrolyl-2-carbonyl; Pyridyl-3-carbonyl; benzenesulfonyl; methoxycarbonyl; ethoxycarbonyl; isobutoxycarbonyl; tert-butoxycarbonyl; 2- (tri-methylsilyl) -ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl; 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl; Benzyloxy-carbonyl; 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl;
R² and R⁶ are independently hydrogen or methyl;
R³ and R⁵ independently of one another are hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, 3-guanidinopropyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl, 2-carboxyethyl, mercaptomethyl, 2- (methylthio ) -ethyl, (1-mercapto-1-methyl) -ethyl, hydroxymethyl, 1-hydroxyethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, N, N-dimethylamino, cyclohexylmethyl, imidazol-4-yl methyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, indol-3-ylmethyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzdioxolan-5-yl) - methyl, 2-thienyl, 2-thienylmethyl, 2- (2-thienyl) -ethyl, 3-thienyl, 3-thienylmethyl, 2- (3-thienyl) -ethyl, 4-chlorobenzyl, 2- (methylsulfinyl) -ethyl, 2- (methylsulfonyl) -ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-methyl-imidazol-4-yl) -methyl, (3-methyl-imidazol-4-yl) -methyl, Phenyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidi nylmethyl, indol-2-ylmethyl, 2-benzo [b] thienylmethyl, 3-benzo [b] thienylmethyl, 2-furylmethyl, cyclohexyl or cyclopentyl;
R⁴ is (C₃-C₁₂) -alkyl; mono- or bicyclic (C₃-C₁₂) -cycloalkyl or (C₃-C₁₂) -cycloalkylmethyl, wherein the cycloalkyl moiety is optionally substituted by (C₁-C₄) -alkyl; (C₆-C₁₀) -aryl-methyl; dithiolanyl; Dithiolanylmethyl; Dithianyl or dithianylmethyl;
R⁷ is hydrogen or together with R¹ and the atoms carrying them, a mono- or bicyclic saturated or partially unsaturated ring system having 5-12 ring members, which contains 1 carbon atom except carbon, which is particularly preferably oxidized to sulfone forms, or together with R⁸ and the atoms carrying them form a thiochroman system whose sulfur atom is particularly preferably oxidized to sulfone, and
n 3-6 means.

The invention further relates to a method for Preparation of compounds of the formula I which is characterized characterized in that one has a fragment with terminal Carboxyl group or its reactive derivative with a corresponding fragment couples with free amino group, optionally for the protection of further functional groups (a) temporarily introduced protecting group (s) splits off and optionally the compound thus obtained in it physiologically acceptable salt.

Fragments of a compound of formula I with a terminal carboxyl group have the following Formulas VI and VII

A-OH (VI)

Fragments of a compound of formula I with a Terminal amino group have the following formulas VIII to X

Methods suitable for producing an amide bond are, z. B. in Houben-Weyl, methods of organic Chemistry, Volume 15/2; Bodanszky et al., Peptide Synthesis, 2nd  ed. (Wiley & Sons, New York 1976) the Gross, Meienhofer, The Pepites: Analysis, synthesis, biology (Academic Press, New York 1979). Preferably, the the following methods are used:

Active ester method with N-hydroxy-succinimide, 1-hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro- 1,2,3-benzotriazine as the alcohol component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with Propanephosphonic anhydride and the mixed anhydride Method with pivaloyl chloride or ethyl chloroformate or isobutyl ester.

Fragments of the formula VI, if they are under

• a) Formula II will fall after the well-known Methods for producing amino acids synthesized;
• b) Formula III shall be taken either from corresponding α-amino acids synthesized, wherein the Chirality center is preserved. Diazotization at -20 ° C to 50 ° C in verd. Mineral acids leads to α-bromocarboxylic acids or via the lactic acid too α-trifluoromethanesulfonyloxy carboxylic acids containing a R¹ and R⁷ bearing nucleophile can be reacted; or
• c) Formula IV, are calculated from the corresponding α-amino acids synthesized, wherein the Chirality center is preserved. Diazotization at -20 ° C to 50 ° C in dilute mineral acids leads to Lactic acids containing an R¹ carrying electrophile can be implemented.

Fragments of formula VII are prepared according to the general known methods for the production of amino acids and Peptides synthesized.

Fragments of Formula X are made from suitable carbohydrates prepared via the corresponding protected γ-lactones.  

First, reaction with a C nucleophile such as one Grignard compound or an alkyllithium compound, followed by aminoglycosidation and reductive ring opening with complex hydrides such as LiAlH₄ or catalytic Hydrogenation.

For the preparation of compounds of formula I required pre- and post-operation such as introduction and Cleavage of protective groups are known from the literature and are z. In T.W. Greene "Protective Groups in Organic Synthesis "(Johne Wiley & Sons, New York, 1981) described. Salts of compounds of the formula I with salt-forming groups are in a conventional manner prepared by z. B. a compound of formula I. with a basic group with a stoichiometric Amount of a suitable acid or compounds of the formula I. with an acidic group with a stoichiometric amount a suitable base is reacted. stereoisomer, in particular diastereomer mixtures, optionally with incurred in the synthesis of compounds of formula I can in a conventional manner by fractionated Crystallization or by chromatography.

The compounds of the formula I according to the invention have enzyme-inhibiting properties, in particular they inhibit Aspartyl proteases such as the renin.

Renin becomes as a result of various stimuli (Volume depletion, sodium deficiency, β-receptor stimulation) of the juxtaglomerular cells of the Nieere into the Bloodstream secreted. There it splits from the Liver excreted angiotensinogens the decapeptide Angiotensin I off. This is explained by the "angiotensin converting enzyme "(ACE) into angiotensin II. Angiotensin II plays an essential role in the Blood pressure regulation, as it directly through the blood pressure  Vascular constriction increases. In addition, it stimulates the Secretion of aldosterone from the adrenal gland and increases this way about the inhibition of sodium excretion that extracellular fluid volume, which in turn too contributes to a blood pressure increase. Inhibitor of enzymatic activity of the renin cause a decreased formation of angiotensin I, which decreased one Formation of Angiotension II. The humiliation the concentration of this active peptide hormone is the direct cause of the hypotensive effect of Renin inhibitors.

The efficacy of renin inhibitors can be assessed by in vitro tests be checked. This will reduce the formation of angiotensin I in different systems (human plasma, purified human secretin).

1. Test principle

For example, human plasma containing both renin and Contains angiotensinogen, is to be tested at 37 ° C with the Incubated compound. This is from angiotensinogen under the action of renin angiotensin I released, the then with a commercially available radioimmunoassay can be measured. The angiotensin release is inhibited by renin inhibitors.

2. Recovery of the plasma

The blood is obtained from volunteers (about 0.5 l per person; Bluko-sampling device of the company ASID Bonz and Sohn, Unterschleißheim) and in partially evacuated bottles collected under ice cooling. The extraction is by Addition of EDTA (final concentration 10 mM) prevented. To centrifugation (rotor HS 4 (Sorvall), 3 500 rpm, 0-4 ° C, 15 minutes; repeat, if necessary) will Carefully pipette the plasma and place in appropriate portions  frozen at -30 ° C. Only plasmas are included in the test used sufficiently high renin activity. Plasmas with low renin activity are caused by a cold treatment (-4 ° C, 3 days) activated (Prorenin → Renin).

3. Execution of the tests

Angiotensin I is administered with the Renin-Maia® kit (Serono Diagnostics S.A., Coinsins, Switzerland). The Incubation of the plasma is indicated after the indicated there Instructions performed:

incubation:
1000 μl plasma (thawed at 0-4 ° C)
100 μl of phosphate buffer (pH 7.4)
(Addition of 10 ^-4 M Ramiprilat)
10 μl PMSF solution
10 μl of 0.1% Genapol PFIC
12 μl DMSO or test preparation

The test preparations are generally dissolved in 100% dimethyl sulfoxide (DMSO) 10 ^-2 M and diluted with water accordingly; the incubation mixture contains max. 1% DMSO.

The batches are mixed in ice and added for 1 hour Incubation in a water bath (37 ° C). From a additional approach without inhibitor will be without further Incubation a total of 6 samples (100 ul each) for Determination of the starting angiotensin I content of the used plasma removed.

The concentrations of the test preparations are chosen so that about the range of 10-90% enzyme inhibition is covered (at least five concentrations). At the end of Incubation time, three 100 μl samples from each batch frozen in pre-cooled Eppendorf tubes on dry ice and at about -25 ° C for angiotensin I determination stored (average of three individual samples).  

4. Angiotensin I Radioimmunoassay (RIA)

It becomes exactly the instructions for use of the RIA kit (Renin-Maia® Kit, Serono Diagnostics S.A., Coinsins, Switzerland).

The calibration curve covers the range of 0.2 to 25.0 ng Angiotensin I per ml. The basic angiotensin I content of the Plasma is subtracted from all readings. The plasma Renin activity (PRA) is expressed as ng Ang I / ml × hour specified. PRA values in the presence of the test substances based on an approach without inhibitor (= 100%) and as% Residual activity indicated. From the plot of% Residual activity against the concentration (M) of the test preparation (logarithmic scale), the IC₅₀ value is read.

The compounds of general formula I described in the present invention exhibit inhibitory effects in concentrations of about 10 ^-5 to 10 ^-10 mol / l in the in vitro test.

Renin inhibitors cause a salt-depleted animals Blood pressure reduction. Because human renin is derived from the renin of other species are used for in vivo testing of Renin inhibitors primates, such as rhesus monkeys, used. Primates Renin and Human Renin are in their Sequence largely homologous. By i. v. Injection of Furosemide is stimulated by an endogenous renin release. Subsequently, the test compounds are administered and their effect on blood pressure and heart rate is measured. The compounds of the present invention are in this case a dose range of about 0.1-5 mg / kg i, v, effective at intraduonal administration by gastroscope in the dose range of about 0.5-50 mg / kg. The in the present invention described compounds of general formula I can as antihypertensives and for the treatment of Heart failure can be used.  

The subject of the invention further includes the use of compounds of the formula I for the preparation of Medicines for hypertension therapy and treatment congestive heart failure.

Pharmaceutical preparations contain an effective amount of Active ingredient of the formula I together with an inorganic or organic pharmaceutically acceptable carrier.

Use can be intranasal, intravenous, subcutaneous, peroral or intraduodenal. The dosage of the active ingredient depends on the warm-blooded species, body weight, age and on the type of application.

The pharmaceutical preparations of the present invention be in known solution, mixing, granulating or Drag coating method produced.

For the oral form of application, the active compounds with the customary additives such as carriers, Stabilizers or inert diluents and mixed by customary methods into suitable administration forms such as tablets, dragees, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers can z. Gum arabic, magnesia, magnesium carbonate, Potassium phosphate, lactose, glucose, Magnesium stearyl fumarate or starch, especially corn starch be used. The preparation can be used both as Dry as well as wet granules done. As oily Carriers or solvents come 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 acceptable Salts, if desired with the customary substances  as solubilizers, emulsifiers or other auxiliaries in solutions, suspensions or emulsions. When Solvents come z. B. in question: water, physiological Saline solutions or alcohols, eg. For example, ethanol, propanediol or glycerol, as well as sugar solutions such as glucose or Mannitol solutions, or even a mixture of the various solvents mentioned.

List of abbreviations used: Ac acetyl Boc tert-butoxycarbonyl BuLi n-butyllithium DC TLC DCC dicyclohexylcarbodiimide DCI Desorption Chemical Ionization DIP diisopropylether DNP 2,4-dinitrophenyl DMF dimethylformamide DMSO dimethyl sulfoxide EE ethyl acetate EGG Electron Impact etoc ethoxycarbonyl FAB Fast atom bombardment H hexane Hep n-heptane HOBt 1-hydroxybenzotriazole Iva isovaleryl M molecular peak MeOH methanol MS mass spectrum MTB Methyl tert-butyl ether Nva norvaline Nle norleucine R. T. room temperature Mp. melting point Sdp _xx Boiling point at xx Torr Thi β-2-thienylalanine THF tetrahydrofuran Z Benzyloxycarbonyl.

The other abbreviations used for amino acids correspond to the usual in peptide chemistry three Letter code as he eg. In Eur. J. Biochem. 138, 9-37 (1984). If not explicitly different are always amino acids of the L-configuration.

The following examples serve to illustrate the present invention, without being limited thereto would.

Example 1 Iva-Phe-Nva - [1-cyclohexylmethyl, 2 (S), 3 (R), 4 (R), 5 (S), 6- pentahydroxy] hexylamide

200 mg of Iva-Phe-Nva [1-cyclohexylmethyl, (2,3-, 5,6- diisopropylidene) -2 (S), 3 (R), 4 (R), 5 (S), 6-pentahydroxy] - hexylamide are dissolved in 10 ml of 85% aqueous trifluoroacetic acid dissolved and stirred for 2.5 hours at R. T. The solvents i. Vak. removed and on silica gel with CH₂Cl₂ / MeOH 10: 1 Chromatograph. 140 mg of the title compound are obtained as a colorless amorphous powder.

R _f (CH₂Cl₂ / MeOH 10: 1) = 0.06
MS (FAB + LiJ): 614 (M + Li)

a) Iva-Phe-Nva- [1-cyclohexylmethyl, (2,3-, 5,6-diisopropylidene) - 2 (S), 3 (R), 4 (R), 5 (S), 6-pentahydroxy] hexylamide

578 mg Iva-Phe-Nva-OH, 229 μl N-ethylpiperidine and 230 ul of triethylamine are dissolved in 25 ml of anhydrous CH₂Cl₂ dissolved at -15 ° C with 204 ul pivaloyl chloride. 10  Stirred minutes at R. T., cooled to -10 ° C and with a Solution of 599 mg of [1-cyclohexylmethyl, (2,3-, 5,6-diisopropylidene) - 2 (S), 3 (R), 4 (R), 5 (S), 6-pentahydroxy] hexylamine in 10 ml of anhydrous CH₂Cl₂. 20 hours are stirred at R. T., the solvent i. Vak. removed and taken up in 150 ml of EE. Three times with 50 ml each KH₂PO₄ solution and three times with 50 ml NaHCO₃ solution washed, the EE phase dried over K₂CO₃ and the Solvency i. Vak. away. Chromatography on silica gel with DIP / MTB 1: 1 provided 200 mg of the title compound as colorless amorphous powder.

R _f (MTB / DIP 1: 1) = 0.10
MS (FAB): 688 (M + 1)

b) [1-Cyclohexylmethyl, (2,3-, 5,6-diisopropylidene) - 2 (S), 3 (R), 4 (R), 5 (S), 6-pentahydroxy] hexylamine

740 mg of N- [1-cyclohexylmethyl, (2,3-, 5,6-diisopropylidene) - 2 (S), 3 (R), 4 (R), 5 (S), 6-pentahydroxy] - Hexyl-benzylamine are dissolved in 20 ml of anhydrous MeOH and under argon with 150 ml Pd / C (10%) and 1.1 g HCO₂NH₄ added. 1.5 hours is heated to reflux, from Catalyst filtered off and the solvent i. Vak. away. 600 mg of the title compound are obtained as a pale yellow oil, which continues to be used without cleaning.

R _f (MTB) = 0.05

c) N- [1-Cyclohexylmethyl, (2,3-, 5,6-diisopropylidene) - 2 (S), 3 (R), 4 (R), 5 (S), 6-pentahydroxy] hexyl-benzylamine

880 mg of 2-benzylamino, 2-cyclohexylmethyl, (3,4-isopropylidene) - 3 (S), 4 (R) -dihydroxy, 5 - [(1,2-isopropylidene) - 1 (S), 2-dihydroxyethyl] -tetrahydrofuran are dissolved in 25 ml dissolved anhydrous THF and treated with 188 mg LiAlH₄. Stirred for 20 hours at R. T., with 50 ml of NaHCO solution and extracted three times with 100 ml of EA each time. over  Na₂SO₄ is dried and the solvent i. Vak. away. 690 mg of the title compound are obtained as a colorless oil.

R _f (MTB / Hep 1: 5) = 0.31
MS (DCI): 448 (M + 1)

d) 2-Benzylamino, 2-cyclohexylmethyl, (3,4-isopropylidene) - 3 (S), 4 (R) -dihydroxy, 5 - [(1,2-isopropylidene) -1 (S), 2- dihydroxyethyl] -tetrahydrofuran

4.65 g of 2-cyclohexylmethyl, (3,4-isopropylidene) -2,3 (S), 4 (R) -trihydroxy, 5 - [(1,2-isopropylidene) -1 (S), 2-dihydroxyethyl] - tetrahydrofuran and 5.7 ml of benzylamine are dissolved in Dissolved 150 ml of anhydrous toluene and at -20 ° C with 910 ul TiCl₄ added. It is stirred for 3 hours at R. T., added with 100 ml of saturated aqueous Na₂CO₃ solution, diluted with 300 ml of EA and washed with KH₂PO₄ solution to pH 5 is reached. The organic phase is washed with Na₂SO₄ dried and the solvent i. Vak. away. Chromatography on silica gel with MTB / Hep 1: 5 provides 1.0 g of the title compound as a colorless oil.

R _f (MTB / Hep 1: 5) = 0.24
MS (DCI): 446 (M + 1)

e) 2-cyclohexylmethyl, (3,4-isopropylidene) -2,3 (S), 4 (R) -trihydroxy, 5 - [(1,2-isopropylidene) -1 (S), 2-dihydroxyethyl] - tetrahydrofuran

5.16 g of (2,3-, 5,6-diisopropylidene) -L-gulonic acid γ-lactone is suspended in 300 ml of diethyl ether and under argon at reflux temperature 1.1 equivalents Cyclohexylmethyl-magensiumbromid in 50 ml of diethyl ether in Course of 2 hours dripped. Subsequently, with 100 ml of saturated aqueous NaHCO₃ solution, extracted twice with 100 ml of EA, the organic phase dried over Na₂SO₄ and the solvent i. Vak. away. 4.9 g of the title compound are obtained as a colorless oil, slightly contaminated with bisadduct.

R _f (DIP) = 0.40
MS (DCI): 357 (M + 1)

f) (2,3-, 5,6-diisopropylidene) -L-gulonic acid γ-lactone

42 g of L-gulonic acid γ-lactone and 100 mg of p-toluenesulfonic acid are submerged in 300 ml of 2,2-dimethoxypropane for 5 hours Reflux heated. After 1 hour, a clear Solution. The volatiles are i. Vak. removed and recrystallized from DIP. This gives 45 g the title compound as colorless crystals, mp.: 144 ° C.

R _f (DIP) = 0.12
MS (DCI): 259 (M + 1)

Claims (7)

1. Compounds of the formula I in which
A is a radical of the formulas II, III or IV R¹ is a₁) (C₃-C₈) -cycloalkyl, (C₄-C₁₀) -bicycloalkyl, (C₈-C₁₂) -tricycloalkyl, (C₃-C₈) -cycloalkyl- (C₁-C₆) -alkyl, (C₄-C₁₀) -bicycloalkyl (C₁-C₆) -alkyl, (C₈-C₁₂) -tricycloalkyl- (C₁-C₆) -alkyl, (C₃-C₈) -cycloalkyl-carbonyl and (C₃-C₈) -cycloalkylsulfonyl, in which in each case the cycloalkyl-, Bicycloalkyl and tricycloalkyl substituents by one or two identical or different radicals from the series Fe, Cl, Br, I, hydroxy, (C₁-C₆) -alkoxy, (C₁-C₆) -alkyl, carboxy, (C₁-C₆) Alkoxycarbonyl, carbamoyl, carboxymethoxy, amino, (C₁-C₆) monoalkylamino, (C₁-C₆) dialkylamino, amino (C₁-C₆) alkyl, (C₁-C₆) alkylamino (C₁-C₆) alkyl, Di- (C₁-C₆) alkylamino (C₁-C₆) alkyl, amidino, hydroxyamino, hydroximino, hydrazono, imino, guanidino, (C₁-C₆) alkyloxysulfonyl, (C₁-C₆) alkyloxysulfenyl, trifluoromethyl, (C₁-C₆) alkylthio -C₄) alkoxycarbonylamino, (C₆-C₁₂) aryl- (C₁-C₄) alkoxycarbonyl-amino substituted can;
Hydrogen, (C₁-C₁₈) alkyl, (C₁-C₁₈) alkanoyl, (C₁-C₁₈) alkoxycarbonyl, (C₁-C₁₈) alkylsulfonyl, (C₁-C₁₈) alkylsulfinyl, wherein the alkyl groups are each protected by optionally protected amino , Trimethylsilyl, hydroxy, mercapto, (C₁-C₄) -alkylthio, halogen, (C₁-C₄) -alkoxy, mono- or di- (C₁-C₈) -alkylamino, carboxy, carbamoyl, guanidino, (C₁-C₄) - Alkoxycarbonyl, (C₁-C₈) alkanoyloxy, phenyl (C₁-C₄) alkoxy or a radical CONR⁸R⁹ may be substituted; (C₁-C₄) alkoxy;
(C₆-C₁₄) aryl, (C₆-C₁₄) aryl- (C₁-C₄) alkyl, (C₆-C₁₄) aryl- (C₁-C₄) alkoxy, wherein the aryl radical in each case by one, two or three Radicals of the group (C₁-C₆) alkyl, amino, mono- or di- (C₁-C₄) alkylamino, amino (C₁-C₄) alkyl, hydroxy (C₁-C₄) alkyl, mono- or di - (C₁-C₄) -alkylamino- (C₁-C₄) alkyl, hydroxy, (C₁-C₄) alkoxy, halogen, formyl, (C₁-C₄) alkoxycarbonyl, carboxamido, mono- or di- (C₁-C₄ ) -alkylaminocarbonyl or nitro;
Het, Het- (C₁-C₄) alkyl, wherein Het represents a 5-, 6- or 7-membered heterocyclic ring which may be benzo-nated and either aromatic, partially hydrogenated or fully hydrogenated and the hetero element one or two radicals of the group N, O, S, NO, SO or SO₂ and by one or two radicals of the group (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₄) alkoxycarbonyl, hydroxy, halogen, amino, Mono- or di- (C₁-C₄) alkylamino may be substituted or a radical NR⁸R⁹ means, wherein
R⁸ and R⁹ are the same or different and are independently hydrogen; (C₁-C₈) alkyl, which may be substituted by amino, (C₁-C₄) alkylamino, di- (C₁-C₄) alkylamino, hydroxy or (C₁-C₄) alkoxy, (C₃-C₇) cycloalkyl ; mercapto; (C₁-C₄) - alkylthio; phenylthio; (C₁-C₄) alkoxycarbonyl; Carboxy, (C₆-C₁₄) -aryl which may be substituted in the aryl radical as described above; Het or het (C₁-C₄) alkyl, wherein Het is as defined above, means or wherein
R⁸ and R⁹ together with the nitrogen atom they carry form a 5- to 12-membered ring which may be mono- or bicyclic and contain, as further ring members, 1 or 2 nitrogen atoms, 1 sulfur atom or 1 oxygen atom and by (C₁-C₄) - Alkyl may be substituted,
or
R¹ a₂) is a radical of the formula V is R ^{1 '} -W (V) wherein R ^{1' is defined} as R¹ under a₁) and W is -CO-, -CS-, -O-CO-, -SO₂-, -SO -, -NH-SO₂-, -NH-CO-, -CH (OH) - or -N (OH) -;
R² and R⁶ independently of one another denote hydrogen or (C₁-C₄) -alkyl,
R³ and R⁵ are independently defined as R¹ under a₁);
R⁴ is (C₃-C₁₂) -alkyl; mono-, bi- or tricyclic (C₃-C₁₈) -cycloalkyl, (C₃-C₁₈) -cycloalkylmethyl, (C₃-C₁₈) -cycloalkylethyl, wherein the cycloalkyl moiety is optionally substituted by (C₁-C₆) -alkyl; dithiolanyl; (C₆-C₁₄) arylmethyl; Dithiolanylmethyl; Dithiolanylethyl; dithianyl; Dithianylmethyl or dithianylethyl;
R⁷ is hydrogen or (C₁-C₈) -alkyl, or together with R¹ or R⁵ and the atoms carrying them form a mono- or bicyclic, saturated or partially unsaturated ring system having 5-12 ring members, which may contain 1 sulfur atom other than carbon, which may optionally be oxidized to the sulfoxide or sulfone; and
n 2-10 means
and their physiologically acceptable salts. 2. Compounds of the formula I according to claim 1, characterized in that
A as defined in claim 1;
R¹ is hydrogen or (C₁-C₁₀) -alkyl; cyclopentyl; cyclohexyl; Cyclopentyl (C₁-C₆) alkyl; Cyclohexyl (C₁-C₆) alkyl; Phenyl (C₁-C₄) alkyl, wherein the phenyl radical is optionally substituted as indicated on page 2; Thienyl or thienyl (C₁-C₄) alkyl, wherein the thiophene may each be substituted by one or two radicals of the group (C₁-C₄) alkyl, (C₁-C₄) alkoxy or halogen, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl (C₁-C₄) alkyl, wherein the pyridine radical is substituted by one or two radicals of the group (C₁-C₄) alkyl, (C₁-C₄) alkoxy or halogen can be means; H₂N- (C₁-C₁₀) alkyl; HO- (C₁-C₁₀) alkyl; (C₁-C₄) alkoxy (C₁-C₁₀) alkyl; (C₁-C₄) alkoxycarbonyl (C₁-C₁₀) alkyl; (C₁-C₈) -alkylsulfonyl; (C₁-C₈) -alkylsulfinyl; (C₁-C₈) -Hydroxyalkylsulfonyl; (C₁-C₈) -hydroxy-alkylsulfinyl; Hydroxy (C₁-C₁₀) alkanoyl; (C₁-C₈) alkanoyloxy (C₁-C₁₀) alkyl; (C₁-C₁₁) -alkanoyl; optionally protected amino (C₁-C₁₁) alkanoyl, such as (3-amino-3,3-dimethyl) propionyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 4-N-tert-butoxycarbonylaminobutyryl, 5- N-tert-butoxycarbonylaminopentanoyl or 6-N-tert-butoxycarbonylaminohexanoyl; Di (C₁-C₇) alkylamino (C₂-C₁₁) alkanoyl; (C₃-C₈) -cycloalkylcarbonyl; amino-substituted (C₃-C₈) -cycloalkyl-carbonyl; amino-substituted (C₃-C₈) -cycloalkyl-sulfonyl, (C₆-C₁₀) -aryl (C₂-C₁₁) -alkanoyl; 2-pyridyl (C₁-C₈) alkanoyl; 3-pyridyl (C₁-C₈) alkanoyl; 4-pyridyl (C₁-C₈) alkanoyl; optionally substituted by halogen, (C₁-C₆) alkyl, (C₁-C₄) alkoxy or (C₁-C₄) alkoxycarbonyl substituted benzoyl; benzenesulfonyl; (C₁-C₁₀) -alkoxycarbonyl, substituted (C₁-C₁₀) -alkoxycarbonyl; or (C₆-C₁₄) aryl- (C₁-C₆) alkoxycarbonyl;
R² and R⁶ independently of one another denote hydrogen or (C₁-C₄) -alkyl,
R³ and R⁵ are independently defined as defined in claim 1 a₁);
R⁴ is (C₃-C₁₂) -alkyl; mono-, bi- or tricyclic (C₃-C₁₈) -cycloalkyl or (C₃-C₁₈) -cycloalkylmethyl, wherein the cycloalkyl moiety is optionally substituted by (C₁-C₄) -alkyl; C₆-C₁₄) arylmethyl; dithiolanyl; Dithiolanylmethyl; Dithianyl and dithinaylmethyl;
R⁷ is hydrogen or methyl, or together with R¹ or R⁵ and the atoms carrying them, a mono- or bicyclic saturated or partially unsaturated ring system having 5-12 ring members, which may contain 1 carbon atom other than carbon, which may optionally be oxidized to the sulfoxide or sulfone can, forms; and
n 2-8, means. 3. Compounds of formula I according to claim 1 and / or 2, characterized in that
R¹ is (C₁-C₈) alkylsulfonyl; (C₁-C₈) -alkylsulfinyl; 2-hydroxyethylsulfonyl; 2-hydroxy-propylsulfonyl; 2-hydroxypropionyl; 3-hydroxypropionyl; 3-hydroxybutyryl; 2-hydroxy-3-methylbutyryl; (C₁-C₈) alkanoyloxy (C₁-C₁₀) alkyl; n-decanoyl; formyl; acetyl; propionyl; Pivaloyl, isovaleryl; isobutyryl; (3-amino-3,3-dimethyl) -propionyl); 4-aminobutyryl; 5-aminopentanoyl; 6-aminohexanoyl; dimethylaminoacetyl; Piperidino-4-carbonyl; Morpholino-4-carbonyl; cyclopropylcarbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl; cyclohexylcarbonyl; 3-Aminocyclobutylcarbonyl; 4-aminocyclohexylcarbonyl; 3-Aminocyclobutylsulfonyl; 4-Aminocyclohexylsulfonyl; phenylacetyl; phenylpropanoyl; phenylbutanoyl; 2-pyridyl (C₁-C₈) alkanoyl; 3-pyridyl (C₁-C₈) alkanoyl; 4-pyridyl (C₁-C₈) alkanoyl; 4-chlorobenzoyl; 4-methylbenzoyl; 2-methoxycarbonylbenzoyl; 4-methoxybenzoyl; Pyrrolyl-2-carbonyl; Pyridyl-3-carbonyl; benzenesulfonyl; methoxycarbonyl; ethoxycarbonyl; isobutoxycarbonyl; tert-butoxycarbonyl; 2- (tri-methylsilyl) -ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl; 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl; Benzyloxy-carbonyl; 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl;
R² and R⁹ independently of one another are especially hydrogen or methyl;
R³ and R⁵ independently of one another are hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, 3-guanidinopropyl, carbamoylmethyl, 2-carbamoylethyl, carboxymethyl, 2-carboxyethyl, mercaptomethyl, 2- (methylthio ) -ethyl, (1-mercapto-1-methyl) -ethyl, hydroxymethyl, 1-hydroxyethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, N, N-dimethylamino, cyclohexylmethyl, imidazol-4-yl methyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, indol-3-ylmethyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzdioxolan-5-yl) - methyl, 2-thienyl, 2-thienylmethyl, 2- (2-thienyl) -ethyl, 3-thienyl, 3-thienylmethyl, 2- (3-thienyl) -ethyl, 4-chlorobenzyl, 2- (methylsulfinyl) -ethyl, 2- (methylsulfonyl) -ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-methyl-imidazol-4-yl) -methyl, (3-methyl-imidazol-4-yl) -methyl, Phenyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidi nylmethyl, indol-2-ylmethyl, 2-benzo [b] thienylmethyl, 3-benzo [b] thienylmethyl, 2-furylmethyl, cyclohexyl or cyclopentyl;
R⁴ is (C₃-C₁₂) -alkyl; mono- or bicyclic (C₃-C₁₂) -cycloalkyl or (C₃-C₁₂) -cycloalkylmethyl, wherein the cycloalkyl moiety is optionally substituted by (C₁-C₄) -alkyl; (C₆-C₁₀) -aryl-methyl; dithiolanyl; Dithiolanylmethyl; Dithianyl or dithianylmethyl;
R⁷ is hydrogen or together with R¹ and the atoms carrying them, a mono- or bicyclic saturated or partially unsaturated ring system having 5-12 ring members, which contains 1 carbon atom except carbon, which is particularly preferably oxidized to sulfone forms, or together with R⁸ and the atoms carrying them form a thiochroman system whose sulfur atom is particularly preferably oxidized to sulfone, and
n 3-6 means. 4. Process for the preparation of a compound of the formula (I) according to one of claims 1 to 3, characterized characterized in that one has a fragment with terminal Carboxyl group or its reactive derivative with a corresponding fragment couples with free amino group, optionally for the protection of further functional groups (a) temporarily introduced protecting group (s) splits off and optionally the compound thus obtained in it Physiologically acceptable salt transferred. 5. Use of a compound according to one of claims 1 to 3 as a remedy. 6. Use of a compound according to one of claims 1 to 3 as a remedy in the treatment of Hypertension and congestive heart failure. 7. Pharmaceutical agent containing a compound according to one of claims 1 to 3.