WO1994014840A1

WO1994014840A1 - Acyclic peptide analogs of the atrial natriuretic peptide, process for producing the same and their use

Info

Publication number: WO1994014840A1
Application number: PCT/EP1993/003431
Authority: WO
Inventors: Klaus-Peter Voges; Rolf Henning; Walter Hübsch; Jan-Bernd Lenfers; Martin Beuck; Gudrun Theiss; Johannes-Peter Stasch; Claudia Hirth-Dietrich
Original assignee: Bayer Aktiengesellschaft
Priority date: 1992-12-18
Filing date: 1993-12-06
Publication date: 1994-07-07
Also published as: DE4242946A1; CA2151961A1; EP0674655A1; JPH08508465A; AU5697094A

Abstract

New acyclic peptides with natriuretic effect have general formula: 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 PEPTIDE ANALOGS OF THE ATRIAL NATRIURETIC PEPTIDE, THEIR PRODUCTION PROCESS AND THEIR USE.

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The present invention relates to new acyclic peptides with a natriuretic effect, processes for their preparation and their use in medicaments, in particular as antihypertensive agents. Two general classes of ANP receptors are known from many publications, the guanylate cyclase-coupled (AIB receptor) and the non-guanylate cyclase coupled (C receptor). The A and B receptors are a 120-140 kDa protein with a transmembrane region which mediates the ANP effect (extracellular) on the cGMP system (intracellular) via the particulate guanylate cyclase. Both types of receptors 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, in vascular, endothelial on 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 retained. In vivo results have shown that C receptors perform a clearance function. Infusion of C-ANF (4-23) into anesthetized or awake rats results in a reversible increase in endogenous ANP plasma levels and for lowering blood pressure (see also Maack et al., Science 238 (1987), 675-678). These effects are comparable to those caused by infusion of ANP (1-28).

A C receptor ligand is also known, which is an ANP molecule shortened to 15 amino acids

H-Aro-Ser-Ser-Cys-Phe-Gly-Gly-Arq-lle-Asp-Arq-Ile -Gly-Ala-Cys-NH ₂ It is also known that the core sequence Arg-Ile-Asp-Arg- Ile (RIDRI) is essential for receptor affinity (see here Lewicki et al., US 4757 048).

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 acyclic peptides 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 is} 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 represents} a radical of the formula

or

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

straight-chain or branched alkyl having up to 8 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 -OC- in which

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

R ^{8 is} hydroxyl, 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 This in turn is substituted by carbon atoms with hydroxy, halogen, nitro, alkoxy up to 8 carbon atoms or substituted 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,

B for a residue of the formula

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

R ^{9 is} hydrogen or a hydroxyl protective group, g is 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, 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

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ^{27 are the} same or different and are aryl having 6 to 10 carbon atoms, which may be up to 3 -substantially the same or different is substituted by halogen, hydroxyl, amino or straight-chain or branched alkoxy or alkoxycarbonyl, each having up to 4 carbon atoms, or

R ¹³ straight-chain or branched alkyl having up to 4 carbon atoms means h, h 'and i are identical or different and are a number 0, 1 or 2,

R ¹⁷ and R ^{18 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or an amino protecting group,

R ^{20 is} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, and

R ^{22 represents} a radical of the formula HO ₃ P-

R ² for a group of the formula t

wherein k represents a number 0, 1 or 2,

R ^{28 has} the meaning of R ³ given above and is the same or different with this,

R ²⁹ and R ^{30 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these,

1 represents a number 0, 1 or 2,

R ³¹ and R ^{32 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 and their 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 are preferably 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-nitro4,5-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl 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-chlorobenzoyl, 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 with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to 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 definition given above generally represents a protective group from the series: tert-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, trimethylsilylbenzylyloxy-nitrobenzylyloxy-2-nitrobenzylyloxy-nitro-2-nitrobenzyl-nitrobenzylyl-nitro-2-nitrobenzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-2-benzyl , 4-methoxybenzyl, formyl, acetyl, trichloroacetyl, 2,4-dimethoxybenzyl, methylthiomethyl, methoxyethoxymethyl, [2- (trimethylsilyl) ethoxy] methyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4 -Methoxybenzoyl. Acetyl, benzoyl, benzyl or methylbenzyl 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

λ

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 is} 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 means hydrogen and

R ^{5 represents} a radical of the formula

or

R ^{5 is} cyclopentyl, cyclohexyl, phenyl or hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, the alkyl being optionally substituted by cyano, hydroxy, guanidyl or by a group of the formula -NR ⁶ R ⁷ or R ⁸ -CO- can in what

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

R ^{8 is} hydroxy, benzyloxy, alkoxy with up to 4 carbon atoms, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy 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, hydroxyl, 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 radical of the formula

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

R ^{9 is} hydrogen, benzyl, benzoyl or straight-chain or branched acyl having up to 6 carbon atoms, g is a number 1, 2 or 3

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

has the meaning of e given above and is the same or different with this 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

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²⁴ , R ²⁵ 'R ²⁶ and R ^{27 are the} same or different and are phenyl or naphthyl, which may be up to 2 times the same or different Fluorine, chlorine, bromine, hydroxy, methoxy, methoxycarbonyl or amino are substituted, or

R ¹³ denotes methyl or ethyl, h, h 'and i are identical or different and represent a number 0, 1 or 2,

R ¹⁷ and R ^{18 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 mean

R ^{20 is} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms

R ² for a group of the formula

where k is a number 0, 1 or 2,

R ^{28 has} the meaning of R ³ given above and is the same or different with this, R ²⁹ and R ^{30 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with these,

1 means a number 0, 1 or 2

R ³¹ and R ^{32 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, 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

wherein a number 1 or 2 means a number 0, 1 or 2 means

R ^{3 is} 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 represents} a radical of the formula

or

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 are hydrogen, formyl, benzyloxycarbonyl, straight-chain or branched alkyl or acyl each having up to 4 carbon atoms or tert-butoxycarbonyl (BOC) mean

R ^{8 is} hydroxy, benzyloxy, alkoxy with up to 3 carbon atoms, cyclopentyloxy, cyclohexyloxy, 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, chlorine or alkoxy with bis can be substituted to 4 carbon atoms, or the alkyl by indolyl, imidazolyl, triazolyl, pyridyl or

Pyrazolyl is substituted, the NH function optionally being protected by methyl, benzyloxymethylene or tert-butyloxycarbonyl (BOC), B for a radical of the formula

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

R ⁹ denotes hydrogen, benzyl or straight-chain or branched acyl having up to 4 carbon atoms and 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 meaning 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

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²⁴ , R ²⁵ , R ²⁶ and R ^{27 are the} same or different and are phenyl or naphthyl, which may be identical or different up to 2 times Fluorine, chlorine, bromine, hydroxy, methoxy, methoxycarbonyl or amino are substituted, or

R ¹⁷ and R ^{18 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 ² for a group of the formula

where k is a number 0, 1 or 2

1 means a number 0, 1 or 2

In addition, processes for the preparation of the compounds of the general formula (I) according to the invention have been found, characterized in that in the case where 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) which is 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 Forniel (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 is either hydrogen, one of the amino protective groups listed above or, depending on W, one of the residues A, B, D, E and / or G by deblocking the amine function and activation of 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:

Suitable solvents are the customary organic solvents which do not change under the reaction conditions. These preferably include organic solvents such as 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, di chloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, 1,3-dimethyltetrahydro2 (1H) pyrimidone (DMPH), 1-methylpyrrolidone, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dichloroethane, dimethylformamide or 1-methylpyrrolidone are particularly preferred.

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

Dimethylformamide is preferred for the activation and coupling steps of process [A]. Methanol, glacial acetic acid and diethyl ether are preferred for washing the resin.

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

The process [B] generally proceeds 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 produces correspondingly larger fragments; protective groups can then optionally be split off or exchanged for other protective groups. The target connections are obtained by repeating this process. Condensation agents, which can also be bases, are preferably used as auxiliaries for the respective peptide couplings, in particular if the carboxyl group is present as an activated anhydride. The usual ones are preferred here Condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethyl-carbodiimide hydrochloride, N-cyclohexyl-N '(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMCT), or carbonyl compounds such as carbonyldumidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 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 isobutylchloroformate or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate.

Process [A] generally runs in a temperature range from + 10 ° C to + 35 ° C, preferably at 20 ° C (room temperature).

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 and VIII are known or can be obtained 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 be produced from one or more amino acid groups with a free amino group by repeating this process with correspondingly larger fragments; protective groups can then optionally be split off or exchanged for other protective groups.

As auxiliaries for the respective peptide couplings and for the introduction of the residues of the formulas (VII) and (IX), preference is given to using condensing agents which can also be bases, 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-dimethylaminoisopropyl) -N'-ethyl-carbodiimide hydrochloride, N are preferred here -Cyclo-hexyl-N '(2-morpholinoethyl) -carbodiimide-metho-p-toluenesulfonate (CMCT), or Carbonyl compounds such as carbonyldumidazole, or 1,2-oxazoumum compounds such as 2-ethyl-5phenyl-1,2-oxazoumum-3-sulfate or 2-tert-butyl-5-methyl-isoxazoumum perchlorate or acylamino compounds such as 2-ethoxy 1-ethoxycarbonyl-1,2-dihydroquinoline, or n-propylphosphonic anhydride, or isobutylchloroformate or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or 2- (1H-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 (VII) and (IX) are known or, in the event that the radicals W and Y also include the above-mentioned substituent B, are in part new and can then be prepared by the methods customary in peptide chemistry, in particular as described in Process [A] are prepared.

The compounds according to the invention show an unforeseeable, valuable 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 medicines for the treatment of pathologically changed 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), which had been deprived of their food but not their water 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 via a bladder 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 surgery, there was an equilibration phase of one hour before collecting urine to determine sodium and cGMP excretion. After two control collection periods of 20 minutes each, the substance to be examined was dissolved and infused in physiological saline solution over 60 minutes. The studies were carried out with 6 animals per group.

Test instructions for the ANP C receptor test

Approximately 10 ⁴ hANP C receptor-transfected CHO cells are sown per well on microtiter plates 2 days 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 conc. Approx. 3 ^* x10 ^-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 lysed overnight in 50 μl 0.2 M NaOH / 1% Triton-X-100. The cell lysate is diluted with 100 μl water, in Pharmacie T-Trays transferred and mixed with 250 ul scintillator for scintillation counting in the beta plate counter

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 effects a 50% inhibition of the specific binding of the radio ligand).

The new active ingredient can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, 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, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are produced, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents can optionally be used 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 of body weight in the case of intravenous administration in order to achieve effective results, and the dosage is approximately in the case of 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's behavior towards the medication, 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 above-mentioned minimum quantity, while in other cases the above-mentioned upper limit must be exceeded. Larger in the case of application It may be advisable to distribute quantities in several individual doses throughout 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 ₂ / ethyl acetate 1: 1

VII: CH ₂ Cl ₂ / methanol / formic acid 90: 10: 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

DIEA: diisopropylethylamide

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

Manufacturing examples

Example 1 (Method A)

4-2- (Naphthoyl-amido) phenylacetyl-L-prolyl-L-isoleucinyl-L-aspartyl-L-ornithinyl-L-isoleucinylcarbamide

The synthesis is carried out on a Milligen 9010 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 with a flow of 20 ml / min DMF in reverse flow. After switching to normal flow, equilibrating at 10 ml / min for 5 min

The 7 vials of the amino acid module are filled:

Pos. 1: Fmoc-AM-OH 1.036 g

TBTU 0.616 g

Pos. 2: Fmoc-L-Ile-OH 0.679 g

TBTU 0.616 g

Pos. 3: Fmoc-L-Om (Boc) OH 0.873 g

TBTU 0.616 g pos. 4: Fmoc-L-Asp (OtBu) -OH 0.790 g

TBTU 0.616 g

Pos. 5: Fmoc-L-Ile-OH 0.679 g

TBTU 0.616 g

Pos. 6: Fmoc-L-Pro-OH 0.648 g

TBTU 0.616 g

Pos. 7: 4-2- (naphthoylamido) phenylacetic acid 0.587 g

TBTU 0.616 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 pipetting needle performs 22 mixing processes by blowing argon over a period of 10 seconds. by. 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 pipetting 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 a reduced flow (6.4 ml / min). After 1.1 minutes, the mixture is then pumped in a circle at a flow of 7 ml / min for 60 minutes. After the end of the coupling period, washing out with DMF at a flow of 7 ml / min for 10 min. In parallel, the pipetting needle is rinsed inside and outside and prepared for the next synthesis step

After 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 50 ml

2.Glacial acetic acid 2 x 50 ml

3. Methanol 3 x 50 ml

4. Diethyl ether 3 x 50 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 mixed with 10 ml of a mixture of TFA, p-cresol and H ₂ O (95: 5: 5,

V / V / V) and incubated 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 filtrate is mixed with 20 times the amount of diethyl ether and the product is precipitated. After centrifugation (3000 rpm, 5 min), the centrifugate is washed with diethyl ether, centrifuged again and dried in a desiccator

The polypeptide is in 10 ml of a mixture of 100 ml of acetonitrile and 900 ml

H ₂ O dissolved. On a preparative Abimed HPLC system, it becomes Lichrosorb

RP-18 (10 μm) separated in a 250 x 32 mm column. Mobile phases are A

(100 ml acetonitrile and 900 ml water / 0.5 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)

Output connections

I. 4-2- (Naphthoylamido) phenylacetic acid ethyl ester

20 g (92.7 mmol) of 4-aminophenylacetate are dissolved in 140 ml of dichloromethane. 687 mg (4.6 mmol) of 4-pyrrolidinopyridine are added, after which a solution of 19.4 g is added dropwise with gentle cooling

(102 mmol) of 2-naphthoyl chloride in 90 ml of dichloromethane. After 4 h at room temperature, 296 ml of 1 M HC1 are added. After extraction with ethyl acetate and washing the organic phase twice with saturated NaHCO ₃ solution, the mixture is dried over Na ₂ SO ₄ and concentrated. 25.4 g of the title compound are obtained. R _f (VI) = 0.5. II. 4-2- (Naphthoylamido) phenylacetic acid

24 g (72 mmol) of compound I are dissolved in 90 ml of dioxane. After adding 45 ml of H ₂ O with 4.5 g of LiOH x H ₂ O (108 mmol) in 60 ml of H ₂ O, saponification takes place overnight. After the dioxane has been distilled off, the pH is adjusted to 1 with 12 M HCl and the precipitated product is filtered off with 1 M

Washed HCl, washed neutral with H ₂ O and then recrystallized from ethanol. 19.7 g yield of the title compound is obtained. R _f (IV) = 0.3. III. Nα-tertiary butyloxycarbonyl-L- (Nδ-benzyloxycarbonyl) ornithinyl- (2-methyl) butylamide

12.5 g (34.1 mmol) of Boc-L-Orn (Z) -OH are mixed with 11.5 g (35.8 mmol)

TBTU mixed and dissolved in 110 ml DMF by adding 6.2 ml (35.8 mmol) DIEA is activated. 4.8 ml (40.9 mmol) of 2-methylbutylamine, dissolved in 5 ml of DMF, are added. After 12 h the DMF is distilled off, the residue is taken up in ethyl acetate and washed alkaline (NaHCO ₃ ) and acidic (KHSO ₄ ). After drying over Na ₂ SO ₄ and crystal solution, 14.7 g of the title compound are obtained. R _f (Va) = 0.5. IV. L- (Nδ-Benzyloxycarbonyl) -ornithinyl- (2-methyl) butylamide, hydrochloride

14.7 g (33.7 mmol) of the compounds III is dissolved in 80 ml of a 1.76 M HCl in glacial acetic acid. After 45 min with exclusion of moisture, CO ₂ and

Isobutane removed in a slight vacuum After precipitation through 1500 ml of diethyl ether, 13.8 g of the title compound are obtained. The splitting off of the BOC group was checked by ¹ H-NMR spectroscopy. V. Tertiarybutyloxycarbonyl-L- (β-benzyloxy) aspartyl-L- (Nδ-benzyloxycarbonyl) ornithinyl- (2-methyl) butylamide

13 g (40.2 mmol) Boc-Asp (OCH ₂ -C ₆ H ₅ ) -OH are dissolved with 14.1 g (43.8 mmol) TBTU in 130 ml DMF.After adding 15.9 ml DIEA (91 , 3 mmol) is activated for 30 min. 13.8 g (36.5 mmol) of compound IV, dissolved in 25 ml of DMF, are added to the activated carboxy component. After 12 h the DMF is distilled off and the residue is taken up in ethyl acetate. The product which has precipitated is filtered off with suction and washed with ethyl acetate. 20 g of crystalline product are obtained. The mother liquor is extracted from basic (NaHCO ₃ ) and acid (KHSO ₄ ) and dried and set for crystallization. Another 3 g of the title compound are obtained. R _f (Va) = 0.5.

VI. L- (ß-Benzyloxy) aspartyl-L- (Nδ-benzyloxycarbonyl) ormithinyl- (2-methyl) - butylamide hydrochloride

23 g (33.9 mmol) of compound V are dissolved in 96 ml (168.5 mmol) of a 1.76 M HCl in glacial acetic acid. The mixture is stirred for 30 minutes with the exclusion of moisture, then CO ₂ and isobutene are removed under a slight vacuum. The solution is added dropwise to 2000 ml of diethyl ether and the product is precipitated as hydrochloride, washed neutral and dried. 14.3 g of the title compound are obtained. The splitting off of the BOC protective group was detected by 1H NMR spectroscopy.

VII. Nα-tertiary butyloxycarbonyl-L-prolyl-L-isoleucinylmethyl ester

15 g (69.8 mmol) Boc-L-Pro-OH are mixed with 24.4 g (76.1 mmol) TBTU and dissolved in 220 ml DMF with the addition of 27.7 ml (159 mmol) DIEA is pre-activated for 30 min. A solution of 11.5 g H-Ile-OMe-HCl in

50 ml (63.5 mmol) of DMF is added and the mixture is coupled at room temperature for 12 h. The DMF is distilled off and the residue is taken up in ethyl acetate. After alkaline (NaHCO ₃ ) and acidic (KHSO ₄ ) washing, the mixture is dried over Na ₂ SO ₄ and concentrated. 25 g of the title compound are obtained. After chromatography on silica gel stationary phase (40 x

5 cm; mobile phases A (10 ml dichloromethane and 990 ml methanol), B (30 ml dichloromethane and 970 ml methanol); Gradient from A to B in 60 min. you get 20.5g of the title association. R _f (IV) = 0.66. VIII.Nα-tertiary butyloxycarbonyl-L-propyl-isoleucine

14.6 g (42.6 mmol) of compound VII are dissolved in 30 ml of dioxane. After adding 25 ml of H ₂ O, 2.7 g (63.9 mmol) of LiOH × H ₂ O, dissolved in 40 ml of H, are added ₂ O, saponified. After 12 h, the dioxane is distilled off at pH 10, extracted twice with ether, and after acidification to pH 3, the mixture is extracted 3 times with ethyl acetate. The product phase is dried over Na ₂ SO ₄ and crystallized from ethyl acetate. 12.2 g of the title compound are obtained. R _f (Vb) = 0.5.

IX. Nα-tertiary butyloxycarbonyl-L-prolyl-L-isoleucinyl-L- (ß-benzyloxy) aspartyl-L- (Nδ-benzoxycarbonyl) ornithinyl- (2-methyl) butylamide

3.74 g (11.4 mmol) of compound VIII are mixed with 3.85 g (12 mmol) of TBTU and dissolved in 40 ml of DMF. After adding 4.5 ml (26 mmol) of DIEA, the mixture is preactivated for 30 min. A solution of 6 g (10.4 mmol) of compound VI, dissolved in 10 ml of DMF, are added and the mixture is coupled for 12 h. After concentration, the residue is partitioned between ethyl acetate and a saturated NaHCO ₃ solution, the organic phase is washed alkaline (NaHCO ₃ ) and acid (KHSO ₄ ). After drying over Na ₂ SO ₄ , the mixture is concentrated. 7.5 g of the title compound are obtained. R _f (Va) = 0.45. L-prolyl-L-isoleucinyl-L- (ß-benzyloxy) aspartyl-L- (Nδ-benzoxycarbonyl) - omithinyl- (2-methyl) butylamide), hydrochloride

7.5 g (8.8 mmol) of the compound IX are mixed with 20 ml of a 1.76 M HCl in glacial acetic acid and stirred for 40 min with exclusion of moisture. After removal of CO ₂ and isobutene in a slight vacuum, it is precipitated by dropping in 1000 ml of diethyl ether . After washing and drying, 4.78 g of the title compound are obtained. The removal of the BOC protecting group was checked by ¹ H NMR spectroscopy Example 2

4-2- (Naphthoylamido) phenylacetyl-L-propyl-L-isoleucinyl-L- (β-benzyloxy) aspartyl-L- (Nδ-benzoxycarbonyl) ornithinyl- (2-methyl) butylamide

2.2 g (7.28 mmol) of compound II are mixed with 2.5 g (7.89 mmol) of TBTU and dissolved with 25 ml of DMF. Activation is carried out by adding 2.6 ml (15.2 mmol) of DIEA. After 30 min, 4.78 g (6.07 mmol) of compound X, dissolved in 10 ml of DMF, are added. After coupling for 12 hours, the procedure is as described for the compound IX specification. 3.1 g of the title compound are obtained, which is uniform according to HPLC, ¹ H-NMR and MS R _f (V) = 0.42.

Example 3

4-2- (Naphthoylamido) phenylacetyl-L-prolyl-L-isoleucinyl-L-aspartyl-L-ornithinyl- (2-methyl) butylamide

3.1 g (3 mmol) of the compound from Example 2 are dissolved in 130 ml of methanol and 20 ml of glacial acetic acid are added. After adding 300 mg of Pd on activated carbon (10%), the mixture is hydrogenated at 3 bar. After suctioning off the catalyst, 500 are evaporated down g Contain product, which is purified from a preparative HPLC system, as described in Example 1. 450 mg of pure product An Vydac RP-18 (10 μ) (150 mm × 3.9 mm) are obtained with a flow of 1.5 ml / min and a gradient as in FIG. 2, the retention time is R _τ = 7, 59 min.

•

-

Claims

1. Acyclic peptides 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 represents} a radical of the formula

or

R ⁵ denotes cycloalkyl with 3 to 8 carbon atoms or aryl with 6 to 10 carbon atoms or hydrogen, or straight-chain or branched alkyl with up to 8 carbon atoms, the alkyl optionally being cyano, hydroxy, guanidyl or 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, straight-chain or branched acyl or alkyl 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 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 having 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 protecting group are,

B for a residue of the formula

stands in what j represents a number 0, 1, 2, 3 or 4,

R ^{9 represents} hydrogen or a hydroxyl protective group, g represents 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

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

R ₁₃ - (CH ₂ ) _h -CO-NH-

R ₁₃ - (CH ₂ ) _h -CO-NH, R ¹⁴ - (CH ₂ ) ₁ -, R ¹⁴ -O- (CH ₂ ), -

R ₁₅ -CH ₂ -NH (R ₁₆ -CH ₂ ) ₂ -N CH,

R ₂₀ O ₂ C-CH ₂

R ₁₇ R ₁₈ N

R ₂₄ -O-CH ₂ -CO-NH

R ₂₅ - CH ₂ -CO-O

R ₂₄ -O-CH ₂ -CO-NH

R ₂₆ - (CH ₂ ) _h -O- R ₂₇ - (CH ₂ ) _h -O-NH

stands,

wherein wherein

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ^{27 are the} same or different and are aryl having 6 to 10 carbon atoms, which may be up to 3 is substituted in the same way or differently by halogen, hydroxy, amino or straight-chain or branched alkoxy or alkoxycarbonyl, each having up to 4 carbon atoms, or

R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms, h, h 'and i are identical or different and denote a number 0, 1 or 2,

R ^{22 represents} a radical of the formula HO ₃ P-,

R ² for a group of the formula

where k is a number 0, 1 or 2,

R ²⁹ and R ^{30 have} the meanings of R ⁴ and R ⁵ given above and are identical or different with them, l denotes a number 0, 1 or 2,

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

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 represents} hydrogen, and

R ^{5 represents} a radical of the formula

or

R ⁵ denotes cyclopentyl, cyclohexyl, phenyl or hydrogen, or

straight-chain or branched alkyl having up to 6 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 ^{8 is} hydroxy, benzyloxy, alkoxy with up to 4 carbon atoms, cyclopropyl, cyclopentyloxy, cyclohexyloxy 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, 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,

represents pyridyl or quinolyl, or

for a rest of the formula

R ₁₃ - (CH ₂ ) _h -CO-NH

R ₁₃ - (CH ₂ ) _h -CO-NH CH, - R ¹⁴ - (CH ₂ ), - R ¹⁴ -O- (CH ₂ ) i-,

R ₁₅ -CH ₂ -NH CH ₂ - (R ₁₆ -CH ₂ ) ₂ -N- -CH ₂ -

R ₂₀ O ₂ C

R ₁₇ R ₁₈ N

R ₂₄ -O-CH ₂ -CO-NH

R ₂₅ -CH ₂ -CO-O

R ₂₄ -O-CH ₂ -CO-NH -

R ₂₆ - (CH ₂ ) _h -O ~ R ₂₇ - (CH ₂ ) _h -O-NH

r V

stands,

wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²⁴ , R ²⁵ 'R ²⁶ and R ^{27 are the} same or different and are phenyl or naphthyl, which may be up to 2 times the same or different Fluorine, chlorine, bromine, hydroxy, methoxy, methoxycarbonyl or amino are substituted, or

R ¹⁷ and R ^{18 are} identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, phenyl, benzyloxycarbonyl (Z) or terL-butoxycarbonyl,

R ²⁰ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

R ² for a group of the formula

wherein k represents a number 0, 1 or 2,

R ³¹ and R ^{32 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, and the like 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

in which f represents a number 1 or 2, e represents a number 0, 1 or 2,

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 represents} a radical of the formula

or

R ⁵ denotes cyclopentyl, cyclohexyl or hydrogen,

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

R ⁶ and R ⁷ independently of one another are hydrogen, formyl, benzyloxycarbonyl, straight-chain or branched

Mean acyl or alkyl each having up to 4 carbon atoms or tert-butoxycarbonyl (BOC),

R ^{8 is} hydroxy, benzyloxy, alkoxy with up to 3 carbon atoms, cyclopentyloxy, cyclohexyloxy, 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, chlorine or Alkoxy can be substituted with up to 4 carbon atoms, 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 and g denotes a number 1, 2 or 3,

stand,

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

represents pyridyl or quinolyl, or

for a rest of the formula

R ₁₃ - (CH ₂ ) _h -CO-NH

R ₁₃ - (CH ₂ ) _h -CO-NH R ¹⁴ - (CH ₂ ) _i - R ¹⁴ -O- (CH ₂ ) ₁ -,

R ₁₅ -CH ₂ -NH - (R ₁₆ -CH ₂ ) ₂ -N

H ₂₀ O ₂ C-CH ₂

R ₁₇ R ₁₈ N

R ₂₄ -O-CH ₂ -CO-NH

R ₂₅ -CH ₂ -CO -O

R ₂₄ -O-CH ₂ -CO-NH, -

R ₂₆ - (CH ₂ ) h, - R27-ICH2) -0-NH

stands,

woπn

R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²⁴ , R ²⁵ , R ²⁶ and R ^{27 are the} same or are different and are phenyl or naphthyl, which are optionally substituted up to 2 times identically or differently by fluorine, chlorine, bromine, hydroxyl, methoxy, methoxycarbonyl or amino, or

R ¹³ denotes methyl or ethyl, h and i are identical or different and represent a number 0 or 1,

R ¹⁷ and R ^{18 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 ² for a group of the formula

or stands

where k is a number 0, 1 or 2, R ^{28 has} the meaning of R ³ given above and is the same or different with this,

1 represents a number 0, 1 or 2,

Process for the preparation of compounds of 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

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

R ^{4 is} hydrogen, and R ^{5 represents} a radical of the formula

or

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 is substituted, which in turn is substituted by hydroxy, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NR ⁶ R ⁷ , wherein

B for a residue of the formula

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

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

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

represents pyridyl or quinolyl, or

for a rest of the formula

XXX

R ₁₃ - (CH ₂ ) _h -CO-NH-

R ₁₃ - (CH ₂ ) _h -CO-NH R ¹⁴ - (CH ₂ ) ₁ _, R ¹⁴ -O- (CH ₂ ) ₁ - _,

R ₁₅ -CH ₂ -NH (R ₁₆ -CH ₂ ) ₂ - N

R ₂₀ O ₂ C -CH ₂

R ₁₇ R ₁₈ N

R ₂₄ -O-CH ₂ -CO-NH

R ₂₅ - CH ₂ -CO-O

R ₂₄ -O-CH ₂ -CO-NH

R ₂₆ - (CH ₂ ) _h , -O y R ₂₇ - (CH ₂ ) _h - _, O-NH

stands,

wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ and R ^{27 are the} same or different and are aryl having 6 to 10 carbon atoms, which may be up to 3 -substituted identically or differently by halogen, hydroxyl, straight-chain or branched alkoxy or alkoxycarbonyl, each having up to 4 carbon atoms or amino, or

R ¹³ denotes straight-chain or branched alkyl having up to 4 carbon atoms, h and i are identical or different and one 21 is 0 or 1,

R ²² denotes a radical of the formula HO ₃ S- or HO ₃ P-,

R ² for a group of the formula

or stands

where k is a number 0, 1 or 2,

1 represents a number 0, 1 or 2,

R ³¹ and R ^{32 are the} same 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 and their salts, characterized in that in the event that R ^{2 is} terminally the free amide group, [A] the respective amino acid sequences of the general formulas (II), (III),

(IV), (V) and (VI) LA-OH (II), MB-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.

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

6. 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 excipients, are converted into a suitable administration form.

7. Use of compounds of general formula (I) according to claim 1 in the control of circulatory diseases.