EP0674654A1

EP0674654A1 - Acyclic, sulphureous peptides as analogs of the atrial natriuretic peptide

Info

Publication number: EP0674654A1
Application number: EP94902693A
Authority: EP
Inventors: Klaus-Peter Voges; Rolf Henning; Jan-Bernd Lenfers; Jürgen Dressel; Martin Beuck; Gudrun Theiss; Johannes-Peter Stasch; Claudia Hirth-Dietrich; Erwin Bischoff
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1992-12-18
Filing date: 1993-12-06
Publication date: 1995-10-04
Also published as: AU5696994A; DE4242945A1; WO1994014839A1; CA2151959A1; JPH08504779A

Abstract

New acyclic peptides with natriuretic effect and reduced basicity have at least one sulphureous group having general formula (I): R1-CO-A-B-D-E-G-R2, in which A, B, D, E, G, R?1 and R2¿ have the meanings given in the description. Also disclosed is a process for producing the same and their use in drugs, in particular as antihypertensive agents.

Description

ACYCLIC, SULFURIZED PEPTIDES AS ANALOGS OF THE ATRIAL NATRIURETIS CHEN PEPTIDES

The present invention relates to new acyclic, sulfur-containing peptides with a natriuretic effect and with reduced basicity, processes for their preparation and their use in medicaments, in particular as antihypertensive agents.

Two general classes of ANP receptors are known from publications, the guanylate cyclase-coupled (A / B receptor) and the non-guanylate cyclase coupled (C-receptor). The A and B receptors are a 120-140 kDA protein with a transmembrane region that mediates the ANP effect (extracellular) on the cGMP system (intracellular) via the particulate guanylate cyclase. Both receptor types bind ANP with high affinity, the affinities for BNP and CNP are different.

ANP-A / B receptors occur for example in endothelial cells, smooth vascular muscle cells as well as in glomerular, mesangial and epithelial cells. The biologically silent C receptor, a homodimer of a 64 kDA transmembrane protein, is common in the renal cortex, vascular, endothelial and smooth muscle cells.

It is known that C receptor ligands can be reduced in size over a wide range without loss of affinity if their core sequence is preserved. In vivo results have shown that C receptors perform a clearance function. Infusion of C-ANF (4-23) into anesthetized or awake rats leads to a reversible increase in endogenous ANP plasma levels and to blood pressure Lowering (see also Maack et al., Science 238 (1987), 675-678; Maack et al. In .: Biological and molecular aspects of atrial factors, edited by P. Needleman, New York 1988, p. 57-76 ). These effects are comparable to those caused by infusion of ANP (1-28). A C receptor hand is also known which is an ANP molecule truncated to 15 amino acids

H-Arq-Ser-Ser-Che-Phe-Gly-Gly-Arq-Ile-Asp-Arg-Ile-Gly-Ala-Cys-NH ₂

It is also known that the core sequence Arg-Ile-Asp-Arg-Ile (RLDRI) is essential for the receptor affinity (cf. Lewicki et al., US 4757048).

In the peptides according to the invention, the position of the first arginine is occupied by non-basic, cyclic amino acids, which surprisingly shows a large increase in affinity

The present invention relates to new acycüsche peptides with at least one sulfur-containing group of the general formula (I)

R ¹ -CO-ABDEGR ² (I),

in which A stands for a direct bond, or

for an amino acid residue of the formula wherein a, b, d and f are the same or different and represent a number 1 or 2, e represents a number 0, 1 or 2,

R ³ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or an amino protecting group,

R ⁴ and R ^{5 are the} same or different and are hydrogen or methyl, or

R ⁴ and R ⁵ together form a 5- or 6-membered carbocyclic, saturated ring, or

R ^{4 is} hydrogen, and R ⁵ cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10

Means carbon atoms or hydrogen, or

straight-chain or branched alkyl having up to 8 carbon atoms, the alkyl optionally being cyano, mercapto, hydroxy,

Guanidyl, is substituted by straight-chain or branched alkylthio having up to 6 carbon atoms or by a group of the formula -NR ⁶ R ⁷ or R ⁸ -OC-, in which

R ⁶ and R ⁷ independently of one another represent hydrogen, formyl, straight-chain or branched alkyl or acyl, each having up to 8 carbon atoms, phenyl or an protecting group for airinos, and

R ^{8 is} hydroxy, benzyloxy, alkoxy having up to 6 carbon atoms, cycloalkyloxy having 3 to 6 carbon atoms, or the group -NR ⁶ R ⁷ mentioned above, or the alkyl optionally by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 Carbon atoms is substituted, which in turn is substituted by hydroxy, halogen, nitro, alkoxy with up to 8 carbon atoms or by the group -NR ⁶ R ⁷ , wherein

R ⁶ and R ^{7 have} the meaning given above, or the alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or indolyl, in which the corresponding -NH functions are optionally protected by alkyl having up to 6 carbon atoms or by an amino protective group,

B for a residue of the formula

where j is a number 0, 1, 2, 3 or 4,

R ⁹ denotes hydrogen, a hydroxyl protective group or straight-chain or branched acyl having up to 6 carbon atoms, g denotes a number 1, 2 or 3,

D, E and G are the same or different and have the meaning of B given above or for a radical of the formula

Stand,

e 'has the meaning of e given above and is the same or different with it, R ^{10 has} the meaning of R ³ given above and is the same or different with this,

R ¹¹ and R ^{12 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these,

R ^{1 represents} straight-chain or branched alkyl having up to 6 carbon atoms, or

represents pyridyl or quinolyl, or

for a rest of the formula

stands in what

R ^{13 represents} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or a sulfur protecting group, h represents a number 1, 2, 3 or 4, i and k are identical or different and represent a number 0 or 1, R ¹⁴ and R ^{15 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or an amino protective group,

R ^{16 has} the meaning of R ⁵ given above and is identical or different with it, l and l 'are identical or different and represent a number 1 or 2, m, n, o and p are identical or different and a number 0, 1 or 2 mean

R ¹⁷ denotes aryl having 6 to 10 carbon atoms, which is optionally substituted up to 3 times in the same or different manner by halogen, hydroxyl or amino,

R ¹⁸ denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or naphthyl, denotes a number 0 or 1, for a group of the formula

NR ²² R ²³ stands,

where r is a number 0, 1 or 2, R ^{19 has} the meaning of R ³ given above and is the same or different with this,

R ²⁰ and R ^{21 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these, s denotes a number 0, 1 or 2,

R ²² and R ^{23 are the} same or different and are an amino protecting group,

Hydrogen or straight-chain or branched alkyl with up to 8 carbon atoms mean, optionally by cycloalkyl with 3 to 6 carbon atoms, phenyl, pyridyl or by

-CO-NH ₂ group is substituted, wherein at least one of the radicals A, D, E or G must always stand for a sulfur-containing amino acid residue or R ¹ must mean a sulfur-containing functional group and its salts. The compounds of the general formula (I) according to the invention have several asymmetric carbon atoms. They can exist independently of one another in the D or L form. The invention includes the optical antipodes as well as the isomer mixtures or racemates. Groups A, B, D, E and G preferably exist independently of one another in the optically pure, preferably in the L-form.

Amino protecting groups in the context of the invention are the usual amino protecting groups used in peptide chemistry.

These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxy Propoxycar bonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert. Butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, cyclohexoxycarbonyl, 1, 1-dimethylethoxycarbonyl, adamantylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl , Menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4 -Chlorbenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl. Physiologically acceptable salts are preferred in the context of the present invention. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts in the context of the present invention are also metal salts, preferably the monovalent metals, and the ammonium salts. Alkali salts such as sodium, potassium, lithium and ammonium salts are preferred.

Hydroxy protective group in the context of the above definition generally stands for a protective group from the series: tert-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert.butyl-dimethylsilyl, tert.-butyldiphenylsilyl, triphenylsilyl, trimethylsilylyl, 2-benzyl, nitrocarbonyl, benzyl Nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-methoxybenzyl, formyl, acetyl, trichloroacetyl, 2,4-dimethoxybenzyl, methylthiomethyl, methoxyethoxymethyl, [2- (trimethylsilyl) ethoxy] methyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4 4-chlorobenzoyl or 4-methoxybenzoyl. Acetyl, benzoyl, benzyl or methylbenzyl are preferred. Sulfur protecting group in the context of the definition given above generally represents a protective group from the series: acetamidomethyl, triphenylmethyl (trityl), tert-butyl, 4-methoxybenzyl, n-butylthio, tert-butylthio, diphenylmethyl, diphenyl-4-pyridylmethyl, 4 -Methylbenzyl, 3,4-dimethylbenzyl, benzyl or 4-picolyl. Triphenylmethyl, tert-butyl and acetamidomethyl are preferred.

Compounds of the general formula (I) in which

A stands for a direct bond, or

for an amino acid residue of the formula

wherein a, b, d and f are the same or different and represent a number 1 or 2, e represents a number 0, 1 or 2,

R ³ denotes hydrogen, methyl, benzyloxycarbonyl (Z) or tert.butoxycarbonyl (BOC), R ⁴ and R ^{5 are} identical or different and are hydrogen or methyl, or R ⁴ or R ⁵ together form a cyclopentyl or cyclohexyl ring, or

R ^{4 is} hydrogen, and

R ⁵ denotes cyclopentyl, cyclohexyl, phenyl or hydrogen, or straight-chain or branched alkyl having up to 6 carbon atoms, where the alkyl optionally by cyano, mercapto, hydroxy, guanidyl, by straight-chain or branched alkylthio having up to 4 carbon atoms or by a group of the formula -NR ⁶ R ⁷ or R ⁸ -OC- is substituted, wherein

R ⁶ and R ⁷ independently of one another are hydrogen, formyl, benzyloxycarbonyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, or tert. Butoxycarbonyl (BOC) stand, and R ^{8 is} hydroxy, benzyloxy, alkoxy with up to 4 carbon atoms, cycloalkyl with 3 to 6 carbon atoms or the above-mentioned group NR ⁶ R ⁷ , or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which in turn is substituted by fluorine, hydroxy, nitro or alkoxy can be substituted with up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, the corresponding -NH functions being optionally protected by alkyl having up to 4 carbon atoms or by an amino protecting group,

B for a residue of the formula

where j is a number 0, 1, 2 or 3,

R ⁹ denotes hydrogen, benzyl, benzoyl or straight-chain or branched acyl with up to 6 carbon atoms, g denotes a number 1, 2 or 3,

D, E and G are the same or different and have the meaning of B given above, or for a radical of the formula stand,

e 'has the meaning of e given above and is the same or different with it,

R ^{10 has} the meaning of R ³ given above and is the same or different with this,

R ¹¹ and R ^{12 have} the meanings of R ⁴ and R ⁵ given above and are the same or different with them, represents straight-chain or branched alkyl having up to 4 carbon atoms, or

represents pyridyl or quinolyl, or

for a rest of the formula

stands in what

R ^{13 represents} hydrogen, alkyl having 1 to 4 carbon atoms, acetamidomethyl or the trityl group, represents a number 1, 2 or 3, i and k are identical or different and represent a number 0 or 1, R ¹⁴ and R ^{15 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, phenyl, benzyloxycarbonyl (Z) or tert-butoxycarbonyl,

R ^{16 has} the meaning of R ⁵ given above and is the same or different with it, l and l 'are the same or different and represent a number 1 or 2, m, n, o and p are identical or different and a number 0, 1 or 2 mean

R ¹ 'denotes phenyl or naphthyl, which are optionally substituted up to 2 times in the same or different manner by fluorine, chlorine, bromine, hydroxy or amino,

R ¹⁸ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, denotes a number 0 or 1,

R ² for a group of the formula

_NR 22 _R 23 stands,

s where r is a number 0, 1 or 2, R ^{19 has} the meaning of R ³ given above and is the same or different with this,

R ²⁰ and R ^{21 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with them, s denotes a number 0, 1 or 2,

R ²² and R ^{23 are the} same or different and are benzyloxycarbonyl (Z), tert-butoxycarbonyl, pivaloyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopentyl, cyclohexyl, phenyl or pyridyl, at least one of which is always used the radicals A, D, E, G or R ¹ must denote a sulfur-containing group, and their salts.

Compounds of the general formula (I) in which

A stands for a direct bond,

for an amino acid residue of the formula

stands,

where f is a number 1 or 2, e represents a number 0 or 1,

R ³ denotes hydrogen, methyl, benzyloxycarbonyl (Z) or tert.butoxycarbonyl (BOC),

R ⁴ and R ^{5 are the} same or different and are hydrogen or methyl, or

R ⁴ and R ⁵ together form a cyclopentyl or cyclohexyl ring, or

R ^{4 is} hydrogen, and

R ⁵ denotes cyclopentyl, cyclohexyl or hydrogen,

or straight-chain or branched alkyl having up to 5 carbon atoms, the alkyl optionally being substituted by cyano, hydroxy, guanidyl or by a group of the formula -NR ⁶ R ⁷ or R ⁸ -CO-, in which

R ⁶ and R ⁷ independently of one another represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, tert-butoxycarbonyl (BOC) or butyl, R ^{8 is} hydroxy, benzyloxy, alkoxy with up to 3 carbon atoms or the group -NR ⁶ R ⁷ mentioned above, or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which in turn is substituted by fluorine, hydroxy, chlorine or alkoxy with up to 4 Carbon atoms can be substituted, or the alkyl is substituted by indolyl, imidazolyl, triazolyl, pyridyl or pyrazolyl, the NH function optionally being protected by methyl, benzyloxymethylene or tert-butyloxycarbonyl (BOC),

B for a residue of the formula

-

in which j represents a number 0, 1, 2 or 3,

R ⁹ denotes hydrogen, benzyl or straight-chain or branched acyl having up to 4 carbon atoms, g denotes a number 1, 2 or 3,

D, E and G are the same or different and have the meaning of B given above, or for a radical of the formula ^stand '

e 'has the meaning of e given above and is the same or different with it,

R ^{10 has} the meanings of R ³ given above and is the same or different with this, R ¹¹ and R ^{12 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these, R ¹ straight-chain or branched alkyl with bis is 4 carbon atoms, or

represents pyridyl or quinolyl, or

for a rest of the formula

stands in what

R ^{13 represents} hydrogen, alkyl having 1 to 4 carbon atoms, acetamidomethyl or the trityl group, h represents a number 1 or 2, i and k are identical or different and represent a number 0 or 1, R ¹⁴ and R ^{15 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, phenyl, benzyloxycarbonyl (Z) or tert-butoxycarbonyl,

R ¹⁷ denotes phenyl or naphthyl which is optionally substituted up to 2 times by the same or different substituents by fluorine, chlorine or bromine,

R ¹⁸ denotes straight-chain or branched alkyl having up to 3 carbon atoms, q denotes a number 0 or 1, R ² denotes a group of the formula

_NR 22 _R 23 stands,

s where r is a number 0, 1 or 2,

R ^{19 has} the meaning of R ³ given above and is the same or different with this, R ²⁰ and R ^{21 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these, s is a number 0, 1 or 2, R ²² and R ^{23 are} identical or different and benzyloxycarbonyl (Z), tert . Butoxycarbonyl, pivaloyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopentyl, cyclohexyl, phenyl or pyridyl, where at least one of the radicals A, D, E, G or R ¹ is always a sulfur-containing group , and their salts.

In addition, processes for the preparation of the compounds of the general formula (I) according to the invention were found, characterized in that in the case that

R ^{2 is} the free amide group, [A] the respective amino acid sequences of the general formulas (II), (III), (IV), (V) and (VI)

L-A-OH (II), M-B-OH (III),

Q-D-OH (IV), T-E-OH (V)

and V-G-OH (VI) in which

A, B, D, E and G have the meaning given above and

L, M, Q, T and V represent one of the amino protective groups listed above, preferably Fmoc, with one another and with the head group of the formula (VII) present in the free acid form

R ¹ -CO ₂ H (VII)

in which

R ^{1 has} the meaning given above, by successive and / or parallel deblocking of the amine function and activation of the respective sequence on a solid phase, or

[B] Compounds of the general formula (VIII)

R ¹ -CO-W-OH (VIII) in which

R ^{1 has} the meaning given above, and

W represents one or more of the radicals A, B, D, E and / or G listed above, with compounds of the general formula (IX) YR ² (IX)

in which

R ^{2 has} the meaning given above and

Y stands either for hydrogen, for one of the amino protecting groups listed above or, depending on W, for one of the residues A, B, D, E and / or G listed above, by deblocking the amine function and activating the carboxylic acid in an inert solvent , in the presence of a base and / or of auxiliaries, by the methods customary in peptide chemistry and the substituents R ¹ and R ² optionally varied by customary methods.

The methods according to the invention can be illustrated by the following formula scheme:

Procedure A:

The usual organic solvents which do not change under the reaction conditions are suitable as solvents. These preferably include organic solvents such as 1,3-dimethyltetrahydro-2 (1H) -pyridinone (DMPH), 1-methylpyrroudone, ethers, for example diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, dichloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dichloroethane, dimethylformamide or 1-methylpyrroudone are particularly preferred.

Dimethylformamide, methane, diethyl ether and glacial acetic acid are preferred for the individual activation and coupling steps of process [A].

Preferred solvents for washing out (process [A]) or crystallization (process [B]) are alcohols, e.g. Methanol, ethanol or n-propanol, halogenated hydrocarbons such as methylene chloride, ethyl acetate, glacial acetic acid, formic acid and ether, e.g. Diethyl ether, diisopropyl ether used.

Methanol, glacial acetic acid and diethyl ether are preferred for washing the resin.

Piperidine, diisopropylethylamine and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate are used as bases and / or auxiliaries in process [A].

The process [B] generally proceeds by reacting a corresponding fragment, consisting of one or more amino acid groups with a free, optionally present in activated form, carboxyl group with a complementary fragment, consisting of one or more amino acid groups, with a correspondingly larger amino group Produces fragments; protective groups can then optionally be split off or exchanged for other protective groups. Condensation agents, which can also be bases, are preferably used as auxiliaries for the respective peptide couplings, in particular if the carboxyl group is activated as the anhydride. The usual condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimemylaminoisopropyl) -N'-ethyl-carbodiimide hydrochloride, N are preferred here -Cyclohexyl-N '(2-morp holmoeth yl) -carbodiirnide-metho-p-toluenesulfonate (CMCT), or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazoumum- 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propylphosphonic anhydride, or isobutylchloroformate, or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or 2- (1-benzotriazol-l-yl) -1,1,3,3-tetra-methyl-uronium tetrafluoroborate.

Process [A] generally takes place in a temperature range from 10 ° C. to 35 ° C., preferably at 25 ° C. The process [B] generally runs in a temperature range from -30 ° C to 35 ° C, preferably from -20 ° C to 25 ° C.

The compounds of the general formula (II), (III), (IV), (V), (VI), (VII) and (VIIa) are known per se and can be obtained by reacting a corresponding fragment, consisting of one or more amino acid groups with a free carboxyl group, optionally present in activated form, with a complementary fragment consisting of one or more amino acid groups with a free amino group and by repeating this process with correspondingly larger fragments; protective groups can then optionally be split off or exchanged for other protective groups.

Condensation agents, which can also be bases, are preferably used as auxiliaries for the respective peptide couplings and for the introduction of formulas (VII) and (IX), in particular if the carboxyl group is present as an anhydride. The usual condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-di methylaminoisopropyl) -N'-emyl-carbodiimide hydrochloride, N-cyclohexyl-N '(2-morphoünoethyl) -carbodiimide-metho-p-toluenesulfonate (CMCT), or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl -5phenyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or n-propylphosphonic anhydride, or isobutyl chloroformate, or benzotriazolyloxy-tris (dimethylamino) phosphomum hexafluorophosphate or 2- (1-benzotriazol-1-yl) -1,1,3,3, -tetramethyluronium tetrafluoroborate.

The reactions can be carried out both at normal pressure and at elevated or reduced pressure (for example 0.5 to 5 bar), preferably at normal pressure.

The compounds of the general formulas (II), (IV), (V), (VI) and (VII) are known per se or can be prepared by a customary method.

The compounds of the general formulas (VII) and (IX) are known in part or, in the event that the radicals W and Y also include the above-mentioned substituent B, are partly new and can then be used according to the methods customary in peptide chemistry, as described in particular are listed under Method [A].

The compounds according to the invention show an unforeseeable, productive spectrum of pharmacological activity. They influence the contraction power of the heart, the tone of the smooth muscles and the electrolyte and fluid balance.

They can therefore be used in medicinal products for the treatment of pathologically altered blood pressure and heart failure, as well as for arteriosclerotic diseases. They can also be used to treat kidney failure, cirrhosis of the liver, ascites, pulmonary edema, cerebral edema, pregnancy edema or glaucoma.

ANP receptor ligands: investigations in vivo

The investigations were carried out with male Wistar rats (300-350 g), from which the feed but not the water was removed the evening before. The animals were anesthetized with thiopental (100 mg / kg i.p.). After tracheotomy, catheters were placed in the femoral artery for blood pressure measurement and in the femoral vein for substance administration. Urine was obtained through a urinary catheter. The rectal temperature of the rats was kept at 37.5 ± 1 ° C using heat lamps. At the end of the procedure, the rats received an injection of 5 ml / kg of physiological saline, which was followed by a continuous infusion at an infusion rate of 1.2 ml / h throughout the investigation. After the surgical procedure, there was an equilibration phase of one hour before the urine was collected to determine sodium and cGMP excretion. After two control collection periods of 20 min each, the substance to be examined was dissolved and infused in physiological saline over 60 min. The studies were carried out with 6 animals per group.

Test instructions for the ANP C receptor test Approx. 10 ⁴ hANP C-receptor transfected CHO cells are sown per well on micro titer plates 2 doses before the start of the experiment. The culture medium is aspirated before the start of the experiment and replaced by 100 μl binding medium (DMEM / 0.1% BSA). 50 μl of the prediluted test substances (max. 1.0% DMSO) and 100 μl binding medium with 25,000 cpm ¹²⁵ I-ANP (final concentration approx. 3 ^x 10 ^-11 mol / l) are subsequently added. After 60 min incubation at 37 ° C., the incubation medium is suctioned off, the cells are washed twice with ice-cold DMEM and then in 50 μl 0.2 M NaOH / 1% Triton-X-100 overnight lysed. The cell lysate is diluted with 100 μl of water, transferred to Pharmacie T trays and mixed with 250 μl of scintillator in the beta plate counter for scintillation counting.

The raw data are analyzed using computer programs for calculating the K _i or IC ₅₀ value (K _i : IC ₅₀ value corrected for the radioactivity used; IC ₅₀ : concentration at which the substance to be examined has a 50% inhibition the specific binding of the radio ligand).

Determination of Enkephaünase activity The test mixture contains in a volume of 110 μl endopeptidase 24.11, KCl 25 mmol / l in Tris / HCL buffer pH 7.4. The enzyme concentration is chosen so that 60% of the ANP 103-126 substrate on rat (Bachern Biochemica) is broken down for a test period. After a pre-circulation of 5 min at 37 ° C, the substance to be examined is added in a volume of 10 μl in 10% DMSO. After an incubation of 30 min at 37 ° C, the reaction is stopped by adding 20 ul 20% trichloroacetic acid and 50 ul acetonitrile. After 10 min, centrifugation is carried out at 15,000 g for 3 min, and the remaining amount of ANP 103-126 is determined in 50 μl of the supernatant by HPLC. A sample which contains 10 μl of 10% DMSO instead of the test preparations is used for comparison

The HPLC analysis is carried out on a micro boron column 2.1 x 100 mm filled with Hypersil ODS 5 μm. The precolumn (4.6 x 10 mm) contains Lichrosorb RP-18 (5 μm). Eluent A: 0.1 mol / l NaCLO ₄ in 0.1% V / VH ₃ PO ₄ ; Eluent B: Acetonitrile gradient from 22 - 50% B in 4 min at a flow rate of 0.5 ml / min, detection at 205 nm.

The new active ingredient can be converted in a known manner into the customary formulations, such as tablets, dragées, piene, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated. The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, it being possible, for example if organic solvents to be used as diluents, to use organic solvents as auxiliary solvents.

The application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously. In general, it has been found to be advantageous to administer amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg body weight for intravenous administration in order to achieve effective results, and the dosage is approximately for oral administration 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of route of administration, on the individual behavior towards the drug, the type of its formulation and the time or interval at which the administration takes place . In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

PC systems used Mobile phases:

I: Petroleum ether / EE 1: 1

II: CH ₂ Cl ₂ / methanol 85:15

III: CH ₂ Cl ₂ / methanol / glacial acetic acid / water 65: 25: 4: 6 IV: CH ₂ Cl ₂ / methanol 95: 5

V: CH ₂ Cl ₂ / methanol 90:10

Va: CH ₂ Cl ₂ / methanol / glacial acetic acid 90: 10: 0.05

Vb: CH ₂ Cl ₂ / methanol / NH ₃ 90: 10: 0.1

VI: Hexane / ethyl acetate 1: 1

Stationary phases: silica gel

HPLC systems used

Mobile phase A: 100 ml acetonitrile in 900 ml water;

Add 0.05% TFA

Mobile phase B: 900 ml acetonitrile in 100 ml water,

Add 0.05% TFA

Gradient 1: in 15 min from A to B, flow 1.5 ml / min Gradient 2: in 8 min from A to B, flow 1.5 ml / min Column: RP 18 (10 μm) (Vydac 218 TPB 10,

150 mm x 3.9 mm)

used abbreviations

TFA: trifluoroacetic acid

EE: ethyl acetate

DMF: dimethylformamide

DLEA: diisopropylethylamine

TBTU: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate

BOC: 1,1-dimethylethoxycarbonyl Starting compounds method B

Example I

S-ß- (1,1-dimethylethoxy) aspartyl-N _α -δ- [1,1-dimethylethoxycarbonyl]) - S-ornithyl-2-methylbutylamide

(Starting from N _α -benzyloxycarbonyl-S-ß- (1,1-dimethylethoxy) aspartyl-N _α - (δ- [1,1-dimethylemoxycarbonyl]) - S-omithyl-2-methyl-butylamide, which is carried out using standard methods accessible in peptide chemistry) 3.52 g (5.8 mmol) of the starting compound are dissolved in 60 ml of methanol. 750 mg of a 10% suspension of Pd on activated carbon are added under argon, followed by 1.8 g (29 mmol) of ammonium formate . The heterogeneous mixture is heated under reflux for 1 hour under a gentle stream of argon. After cooling, it is suctioned off through diatomaceous earth and the filtrate is concentrated. The residue is partitioned between trichloromethane and water. The organic phase is concentrated under high vacuum. 2.69 g of the title compound are obtained.

R _f (III): 0.7 (TMD, ninhydrin) Example II

1,1-dimethylethoxycarbonyl-p-aminophenylacetic acid

40 g of p-aminophenylacetic acid (265 mmol) are dissolved in 500 ml of dioxane / H ₂ O (1/1). The solution is adjusted to pH 10 with 2 N NaOH. 116 g (530 mmol) of bis (1,1-dimethylethyl) dicarbonate are then introduced, and the pH is kept at pH 10 by adding a further 2 N NaOH. After 20 h, the dioxane is removed by rotary evaporation, and the excess bis (1,1-dimethylethyl) dicarbonate is removed by extraction with diethyl ether at pH 10. After acidification to pH 2.0 with saturated, aqueous KHSO ₄ solution, the product is filtered off in crystalline form and washed with cold water. After drying over KOH, the yield is: 58.3 g of the title compound.

R _f (II) = 0.63

Example III

N _α -1,1-dimethylethoxycarbonyl-S-prolyl-N _α -S-isoleucinylbenzyl ester

61.3 g (285 mmol) N _α -1,1-dimethylethoxycarbonylproün are mixed with 100.8 g (31.4 mmol) TBTU and dissolved in 100 ml DMF. To activate 109 ml (62.7 mmol) DLEA are added. 107 g (415 mmol) of S-isoleucine benzyl ester hydrochloride are dissolved in DMF. After 30 minutes, the two solutions are combined and stirred for 12 hours. After concentration, the residue is taken up in EA and washed (2 x with 10% NaHCO ₃ solution, 1 x with H ₂ O, 3 times with ge saturated KHSO ₄ solution). After drying over Na ₂ SO ₄ , the mixture is concentrated. The product is produced as hard foam. The crude product is cleaned on a silica gel column (60 x 10 cm), a gradient of the mixtures petroleum ether / EE 7: 1 -> 1: 1 is used as a mobile phase over a period of 1 hour at a flow rate of 30 ml / min. 98 g of pure product are obtained

R _f (I): 0.48

Example IV S-Prolyl-N _α -S-isoleucinylbenzyl ester, hydrochloride

76.1 g (182 mmol) of the compound from Example III are mixed with 480 ml (720 mmol) of a solution of HCl in glacial acetic acid (1.5 N). After 1 h at room temperature, the mixture is concentrated and taken up again 3 times with dioxane and concentrated The residue is lyophilized from H ₂ O; 77.2 g of a white foam are obtained. The completeness of the Boc aspect was checked by NMR spectroscopy

Example V p- (1,1-Dimethylethoxycarbonyl) aminophenylacetyl-N _α -S-prolyl-N _α -S-isoleucinyl-benzyl ester

20.8 g (82.8 mmol) of the compound from Example II are mixed with 27.7 g (86.3 mmol) of TBTU. The mixture is dissolved in 200 ml of DMF with the addition of 36 ml (207 mmol) of DLEA. After 30 min, 2.45 g (69 mmol) of the compound from Example IV, dissolved in DMF, are added. After 12 hours, the mixture is worked up as described in Example III. 24.1 g of the title compound are obtained.

R _f (IV) = 0.4

Example VI p- (1,1-Dimemylethoxycarbonyl) aminophenylacetyl-N _α -S-prolyl-N _α -S-isoleucine

24.1 g (43.7 mmol) of the compound from Example V are dissolved in 250 ml of methanol and 1 g of a 10% suspension of Pd on activated carbon is added. The heterogeneous mixture is hydrogenated for 4 h in a 1 l -para apparatus at 3.6 bar H ₂ . After the reaction has ended, the product is filtered off with suction and the solvent is evaporated down. 18.5 g of a rigid foam are obtained.

R _f (Vb) = 0.5)

Example VII p- (1,1-Dimemylethoxycarbonyl) arninophenylacetyl-N _α -S-prolyl-N _α -S-isoleucinyl-N _α -S- (ß- [1,1-dimethylethoxy] aspartyl) -N _α -S- (δ- [1,1-dimethylethoxycarbonyl]) ornithyl-2-methylbutylamide

18.5 g (40.1 mmol) of the compound from Example VI are mixed with 14.18 g (44.1 mmol) of TBTU. The mixture is dissolved in 200 ml DMF with the addition of 10.5 ml (60.15 mmol) DIEA. After 30 min, a solution of 19.9 g (42.1 mmol) of the compound from Example I is added. Working up takes place after a coupling time of 12 h as described under Example III. 30 g of the title compound are obtained.

R _f (IV) = 0.4

Example VIII p-Arninophenylacetyl-N _α -S-prolyl-N _α -S-isoleucinyl-N _α -S- (ß- [1,1-dimethylethoxy] aspartyl) -N _α -S- (δ- [1 , 1-dimethylethoxycarbonyl]) ornithyl-2-methylbutylamide hydrochloride CO-Ile-Asp [OC (CH ₃ ) ₃ ] Orn [CO-OC (CH ₃ ) ₃ ] NH x HCl 30 g (32.7 mmol) of the compound from Example VII are reacted as described in Example IV. 29.5 g of the title compound are obtained.

R _f (Va) = 0.45

Example IX

4-thia-5,5,5-triphenylpentanoic acid

8.7 ml (100 mmol) of 3-mercaptopropionic acid are dissolved in 140 ml of trichloromethane. 12.1 ml (100 mmol) of 1-methylpiperidine are added dropwise, followed by a solution of 41.81 g (150 mmol) of trityl chloride in 50 ml of trichloromethane. After 1 h the mixture is extracted (twice with 5% NaHCO ₃ solution; once with H ₂ O; once with saturated KHSO ₄ solution), then washed neutral with H ₂ O. The organic phase is dried (Na ₂ SO ₄ ) and concentrated. The residue is chromatographed on silica gel (30 × 8 cm) using a gradient of dichloromethane / methanol 25: 1 → 9: 1 in 1 h. 16, 16 g of the title compound are obtained.

R _f (V) = 0.68 Example X

4-thia-5,5,5-triphenylpentanoyl-N _α -S-phenylalanylbenzyl ester

(C ₆ H ₅ ) ₃ CS- (CH ₂ ) ₂ -CO-NH At 0 ° C., 5 g (14.3 mmol) of the compound from Example IX are mixed with 4.8 g (15.06 mmol) of TBTU and in 80 ml of DMF with the addition of 3.75 ml (21.5 mmol) of DIEA solved. 4.6 g (15.8 mmol) of phenylalanine benzyl ester, hydrochloride are dissolved in DMF and 2.75 ml (15.7 mmol) of DIEA are added. The solution is cooled to 0 ° C. and added to the 1st solution. After 5 hours, the mixture is worked up as described in Example III. 7.8 g of the title compound are obtained.

R _f (V) = 0.5

Example XI

4-thia-5,5,5-triphenylpentanoyl-N _α -S-phenylalanine

(C ₆ H ₅ ) ₃ CS- (CH ₂ ) ₂ -CO-NH

5 g (8.5 mmol) of the compound from Example X are dissolved in 30 ml of dioxane, mixed with 14 ml of H ₂ O. The mixture is cooled to 0 ° C. and mixed at 0 ° C. with a solution of 530 mg (12.8 mmol) LiOH x H ₂ O in 10 ml H ₂ O. The mixture is allowed to come to RT and saponified for 48 h. Then dioxane is concentrated. At pH 10 the mixture is extracted twice with diethyl ether, then at pH 2.0 three times with EA. After drying over Na ₂ SO ₄ and concentration, 3.0 g of the title compound are obtained.

R _f (Va) = 0.54

Preparation Examples Example 1 (Process A) S- (2-acetylthiomethyl-3-phenyl) propanoyl-glycinyl-glycinyl-S-prolyl-S-isoleucinyl-S-aspartyl-S-arginyl-S-isoleucinylamide

The synthesis is carried out on a Milligen 90 continuous flow synthesizer. The synthesis column is filled with 1.6 g of dry Tentagel-S-NH ₂ resin. After assembly, the column is packed in reverse flow with a flow of 20 ml / min DMF. After switching to normal flow, equilibrate at 10 ml / min for 5 min. The 9 vials of the amino acid module are filled

Pos. 1: Fmoc-AM-OH 1.520 g

TBTU 0.904 g

Pos. 2: Fmoc-L-Ile-OH 0.995 g

TBTU 0.904 g

Pos. 3: Fmoc-L-OArg (Pmc) OH 1.865 g

TBTU 0.904 g

Pos. 4: Fmoc-L-Asp (OtBu) -OH 1.159 g

TBTU 0.904 g

Pos. 5: Fmoc-L-Ile-OH 0.995 g

TBTU 0.904 g

Pos. 6: Fmoc-L-Pro-OH 0.951 g Pos. 7: Fmoc-Gly-OH 0.837 g

TBTU 0.904 g

Pos. 8: Fmoc-Gly-OH 0.837 g

TBTU 0.904 g item 9:

0.626 g

TBTU 0.904 g The synthesis is carried out as follows:

1. Amino acid module

The Fmoc amino acids are dissolved together with TBTU in 6.4 ml of a 0.6 M solution of diisopropylethylamine in DMF. After pipetting in the solvent, the pipette needle carries out 22 mixing processes by blowing in argon over a period of 10 seconds.

2. Automatic synthesizer

At a flow of 7 ml / min, the resin to remove the Fmoc protecting group is washed with a 0.5 N piperidine solution in DMF at a flow of 7 ml / min for 7 min. The piperidine is washed out by washing with DMF at a flow of 7 ml / min. The pipette needle is washed inside and outside with DMF and pipettes the activated Fmoc-amino acid into the sample loop. After the entire 6.4 ml sample has been taken up, the contents of the sample loop are pumped into the system at reduced flow (6.4 ml / min). After 1.1 min, pumping is carried out in a circle for 60 min at a flow of 7 ml / min. After the end of the coupling period, washing out with DMF for 10 min at a flow of 7 ml / min. In parallel, the pipetting needle is rinsed inside and outside and prepared for the next synthesis step. At the end of the synthesis cycles, the resin is rinsed out of the synthesis column and washed out on a frit

1. Methanol 3 x 75 ml

2.Glacial acetic acid 2 x 75 ml

3. Methanol 3 x 75 ml

4. Diethyl ether 3 x 75 ml.

After drying in a desiccator, 2.01 g of peptide resin are obtained. With larger batches, the volume of the washing processes is increased accordingly. The resin is incubated with 20 ml of a mixture of TFA, thioanisole, dithiothreitol, phenol and water (5: 5: 2.5: 5: 2) and cleaved for 1 h at room temperature.

The TFA peptide solution is then suctioned off and the resin is washed 3 times with 50 ml of TFA each.

The feed is mixed with 20 times the amount of diethyl ether and the product is precipitated. After centrifugation (3000 μpm, 5 min), the centrifugate is washed with diethyl ether, centrifuged again and dried in a desiccator. The polypeptide is dissolved in 10 ml of a mixture of 100 ml of acetonitrile and 900 ml of H ₂ O. It is separated on a preparative Abimed HPLC system on Lichrosorb RP-18 (10 μm) in a 250 x 32 mm column. Mobile phases are A (100 ml acetonitrile and 900 ml water) 10.5 ml TFA and B (900 ml acetonitrile and 100 ml water / 0.5 ml TFA). The gradient is run at a flow of 30 ml / min (see Fig. 1).

178 mg of peptide are obtained (R _f = 7.43)

Example 2

S- (2-mercaptomethyl-3-phenyl) propanoyl-glycinyl-glycinyl-S-prolyl-S-isoleucinyl-S-arpartyl-S-arginyl-S-isoleucinylamide 350 g (0.37 mmol) of the compound from Example 1 are dissolved in 14 ml of methanol. After the addition of 350 μl of ethyl mercaptan, 20 mg (0.48 mmol) of LiOH × H ₂ O in 5 ml of H ₂ O are saponified. After 4 hours at RT, the mixture is neutralized and, as described in Example 1, separated on a preparative HPLC system. 230 mg of the title compound are obtained

R _f = 6.21

(Method [B]) Example 3

4-Thia-5,5,5-triphenylpentanoyl-N _α --S-phenylalanyl-p-aminophenylacetyl-N _α - S-propyl-N _α -S-isoleucinyl-N _α -S- (ß- [1.1 -dimethylethoxy] aspartyl) -N _α --S- (δ- [1,1-dimethylethoxycarbonyl]) ornithyl-2-methylbutylamide

(C ₆ H ₅ ) ₃ CS (CH ₂ ) ₂ -CO-NH

3.0 g (6.05 mmol) of the compound from Example XI are mixed with 2.13 g (6.66 mmol)

TBTU mixed and dissolved in 20 ml DMF by adding 1.05 ml (1.5 mmol)

DIEA the solution is activated. 6.05 g (6.4 mmol) of the compound from Example

VIII are dissolved in DMF and added to the activated solution. After 24 h at room temperature, the mixture is worked up as described in Example III

5.06 g of the title compound. Example 4

S-mercaptopropanoyl-N _α -S-phenylalanyl-p-aminophenylacetyl-Nα -prolyl-N _α - S-isoleucmyl-N _α -S-aspartyl-N _α -S-ornithyl-2-methylbutylamide

5 g of the compound from Example 3 are dissolved in 30 ml of a mixture of 85% TFA, 5% H ₂ O, 5% p-cresol and 5% dithiothreitol. After 2 hours, the solution is poured into 2.5 l of cold diethyl ether. The peptide is centrifuged off and the centrifuge is made ether-free in HV. The crude peptide is dissolved in 20% acetonitrile / H ₂ O and on a preparative HPLC system with a gradient of 20% ->

60% acetonitrile separated in 30 min. 2.5 g of the title compound are obtained.

Claims

1. Acyclic peptides with at least one sulfur-containing group of the general formula (I)

R ¹ -CO-ABDEGR ² (I),

in which A stands for a direct bond, or

for an arriino acid residue of the formula

R ^{3 represents} hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or an amino protecting group,

R ⁴ and R ^{5 are the} same or different and are hydrogen or methyl, or R ⁴ and R ⁵ together form a 5- or 6-membered carbocyclic, saturated ring, or

R ^{4 represents} hydrogen, and R ⁵ cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10

Means carbon atoms or hydrogen, or

R ⁶ and R ⁷ independently of one another represent hydrogen, formyl, straight-chain or branched alkyl or acyl each having up to 8 carbon atoms, phenyl or an amino protecting group, and

R ^{8 is} hydroxy, benzyloxy, alkoxy having up to 6 carbon atoms, cycloalkyloxy having 3 to 6 carbon atoms, or the group -NR ⁶ R ⁷ mentioned above, or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in turn is substituted by hydroxy, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NR ⁶ R ⁷ , in which

R ⁶ and R ^{7 have} the meaning given above, or the alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or indolyl, in which the corresponding -NH functions are optionally protected by alkyl having up to 6 carbon atoms or by an amino protecting group are,

B for a residue of the formula

where j is a number 0, 1, 2, 3 or 4,

R ⁹ denotes hydrogen, a hydroxyl protective group or straight-chain or branched acyl having up to 6 carbon atoms, g denotes a number 1, 2 or 3, D, E and G are the same or different and have the meaning of B given above or for a radical of the formula

stand,

e 'has the meaning of e given above and is the same or different with it, R ^{10 has} the meaning of R ³ given above and is the same or different with it,

represents pyridyl or quinolyl, or

for a rest of the formula

/

stands in what

R ¹³ denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or a sulfur protecting group, h denotes a number 1, 2, 3 or 4, i and k are the same or different and represent a number 0 or 1,

R ¹⁴ and R ^{15 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or an amino protective group,

R ¹⁸ denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or naphthyl, q denotes a number 0 or 1,

R ² for a group of the formula

NR ²² R ²³ stands,

R ²² and R ^{23 are} identical or different and represent an amino protecting group, hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, phenyl, pyridyl or by the -CO-NH ₂ group is, at least one of the radicals A, D, E or G must always stand for a sulfur-containing amino acid residue or R ¹ must mean a sulfur-containing functional group and its salts. 2. Compounds of general formula (I) according to claim 1, in which

A stands for a direct bond, or

for an amino acid residue of the formula

in which a, b, d and f are identical or different and denote a number 1 or 2, denote a number 0, 1 or 2,

R ³ denotes hydrogen, methyl, benzyloxycarbonyl (Z) or tert-butoxycarbonyl (BOC),

R ⁴ and R ^{5 are the} same or different and are hydrogen or methyl, or

R ⁴ or R ⁵ together form a cyclopentyl or cyclohexyl ring, or

R ^{4 is} hydrogen, and R ⁵ denotes cyclopentyl, cyclohexyl, phenyl or hydrogen, or

straight-chain or branched alkyl having up to 6 carbon atoms, the alkyl optionally by cyano, mercapto, hydroxy, guanidyl, by straight-chain or branched alkylthio having up to 4 carbon atoms or by a group of the formula -NR ⁶ R ⁷ or R ⁸ -OC - is substituted, in which

R ⁶ and R ⁷ independently of one another are hydrogen, formyl, benzyloxycarbonyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, or tert.

Butoxycarbonyl (BOC) and R ^{8 are} hydroxy, benzyloxy, alkoxy with up to 4 carbon atoms,

Cycloalkyl having 3 to 6 carbon atoms or the above-mentioned group NR ⁶ R ⁷ , or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which in turn by fluorine, hydroxy, nitro or

Alkoxy can be substituted with up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, the corresponding -NH functions being optionally substituted by alkyl having up to 4

Carbon atoms or are protected by an amino protecting group, B for a residue of the formula

where j is a number 0, 1, 2 or 3,

D, E and G are the same or different and have the meaning of B given above, or for a radical of the formula

stand,

e 'has the meaning of e given above and is the same or different with it,

R ^{10 has} the meaning of R ³ given above and is the same or different with this, R ¹¹ and R ^{12 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these,

R ^{1 represents} straight-chain or branched alkyl having up to 4 carbon atoms, or

represents pyridyl or quinolyl, or

for a rest of the formula

stands, wherein

R ¹³ denotes hydrogen, alkyl having 1 to 4 carbon atoms, acetamidomethyl or the trityl group, h is a number 1,

2 or 3 means i and k are the same or different and represent a number 0 or 1, R ¹⁴ and R ^{15 are the} same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, phenyl, benzyloxycarbonyl (Z) or tert .Butoxycarbonyl, R ^{16 has} the meaning of R ⁵ given above and is the same or different, l and l 'are the same or different and represent a number 1 or 2, m, n, o and p are identical or different are and represent a number 0, 1 or 2,

R ¹⁷ denotes phenyl or naphthyl, which are optionally substituted up to 2 times in the same or different manner by fluorine, chlorine, bromine, hydroxy or amino,

R ¹⁸ denotes straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, q denotes a number 0 or 1,

R ² for a group of the formula where r is a number 0, 1 or 2,

R ^{19 has} the meaning of R ³ given above and is the same or different with this,

R ²² and R ^{23 are the} same or different and benzyloxycarbonyl (Z), tert. Butoxycarbonyl, pivaloyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally by cyclopentyl,

Cyclohexyl, phenyl or pyridyl is substituted, wherein at least one of the radicals A, D, E, G or R ¹ must always mean a sulfur-containing group, and their salts.

3. Compounds of general formula (I) according to claim 1, in which

A stands for a direct bond,

for an amino acid residue of the formula

wherein f represents a number 1 or 2, e represents a number 0 or 1,

R ⁴ and R ^{5 are the} same or different and are hydrogen or methyl, or

R ⁴ and R ⁵ together form a cyclopentyl or cyclohexyl ring, or

R ^{4 is} hydrogen, and

R ⁵ denotes cyclopentyl, cyclohexyl or hydrogen,

or straight-chain or branched alkyl having up to 5 carbon atoms, wherein the alkyl may optionally be substituted by cyano, hydroxy, guanidyl or by a group of the formula -NR ⁶ R ⁷ or R ⁸ -CO-, wherein

R ⁶ and R ⁷ independently of one another represent hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, tert-butoxycarbonyl (BOC) or butyl,

R ^{8 is} hydroxy, benzyloxy, alkoxy with up to 3 carbon atoms or the group -NR ⁶ R ⁷ mentioned above, or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which in turn is substituted by fluorine, hydroxy, chlorine or alkoxy with up to 4 Carbon atoms can be substituted, or the alkyl is substituted by indolyl, imidazolyl, triazolyl, pyridyl or pyrazolyl, the NH function optionally being protected by methyl, benzyloxymethylene or tert-butyloxycarbonyl (BOC),

B for a residue of the formula

stands in what j represents a number 0, 1, 2 or 3,

stand, e 'has the meaning of e given above and is the same or different with it,

R ^{10 has} the meanings of R ³ given above and is identical or different with this, R ¹¹ and R ^{12 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these,

represents pyridyl or quinolyl, or

for a rest of the formula stands in what

R ^{13 represents} hydrogen, alkyl having 1 to 4 carbon atoms, acetamidomethyl or the trityl group, h represents a number 1 or 2, i and k are the same or different and represent a number 0 or 1,

R ¹⁴ and R ^{15 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, phenyl, benzyloxycarbonyl (Z) or tert-butoxycarbonyl,

R ¹⁸ denotes straight-chain or branched alkyl having up to 3 carbon atoms, denotes a number 0 or 1,

R ^{2 represents} a group of the formula

R ²² and R ^{23 are the} same or different and are benzyloxycarbonyl (Z), tert-butoxycarbonyl, pivaloyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopentyl, cyclohexyl, phenyl or pyridyl, always at least one of the radicals A, D, E, G or R ^{1 represents} a sulfur-containing group, and their salts.

4. Process for the preparation of compounds of the general formula (I)

R ¹ -CO-ABDEGR ² (I),

in which

A stands for a direct bond, or

R ⁴ and R ^{5 are the} same or different and are hydrogen or methyl, or

Means carbon atoms or hydrogen, or

R ⁶ and R ^{7 have} the meaning given above, or the alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or indolyl, in which the corresponding -NH functions are optionally protected by alkyl having up to 6 carbon atoms or by an amino protecting group,

B for a residue of the formula

where j is a number 0, 1, 2, 3 or 4,

^{You see}

represents pyridyl or quinolyl, or

for a rest of the formula

stands in what

R ^{16 has} the meaning of R ⁵ given above and is the same or different with this,

1 and 1 'are identical or different and represent a number 1 or 2, m, n, o and p are identical or different and represent a number 0, 1 or 2,

R ¹⁷ denotes aryl having 6 to 10 carbon atoms, which may be up to 3 times identical or different through halogen,

Hydroxy or amino is substituted,

R ¹⁸ denotes straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or naphthyl, denotes a number 0 or 1,

R ² for a group of the formula

NR ²² R ²³ stands,

in which a number denotes 0, 1 or 2, R ^{19 has} the meaning of R ³ given above and is the same or different with this,

R ²⁰ and R ^{21 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these, denotes a number 0, 1 or 2,

R ²² and R ^{23 are} identical or different and represent an amino protecting group, hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, phenyl, pyridyl or by the -CO-NH ₂ group , where at least one of the radicals A, D, E or G must always stand for a sulfur-containing amino acid residue or R ¹ must mean a sulfur-containing functional group, characterized in that in the case of R ^{2 the} end position is the free amido group [A] the respective amino acid sequences of the general formulas (II), (III),

(IV), (V) and (VI)

L-A-OH (II), M-B-OH (III),

Q-D-OH (IV), T-E-OH (V)

and V-G-OH (VI) in which

A, B, D, E and G have the meaning given above and

R ¹ -CO ₂ H (VII)

in which

[B] Compounds of the general formula (VIII)

R ¹ -CO-W-OH (VIII) in which

R ^{1 has} the meaning given above, and

in which

R ^{2 has} the meaning given above and

Y represents either hydrogen, one of the amino protecting groups listed above or, depending on W, one of the residues A, B, D, E and / or G listed above, by deblocking the amine function and activating the carboxylic acid in an inert solvent , in the presence of a base and / or of auxiliaries, by the methods customary in peptide chemistry and the substituents R ¹ and R ² optionally varied by customary methods.

5. Compounds of general formula (I) according to claim 1 for use in combating diseases.

6. Medicament containing at least one compound of general formula (I) according to claim 1.

7. A process for the preparation of medicaments, characterized in that compounds of the general formula (I) according to claim 1, if appropriate using conventional auxiliaries and additives, are converted into a suitable application form. Use of compounds of the general formula (I) according to spoke 1 in the manufacture of medicaments for combating high blood pressure.