WO1992006998A1 - Cyclopeptides, a method of preparing them, and their use as drugs - Google Patents

Abstract

The invention concerns cyclopeptides of general formula (I), and their salts, in which the amino-acid units An to Kn are as defined in the description. The invention also concerns the preparation and the use of such cyclopeptides. The new compounds are ANP-agonistic.

Description

 Cyclopeptides, processes for their preparation and their use as medicines

The invention relates to new cyclopeptides made from natural and unnatural amino acid residues

are built, their manufacture and their use as medicines. The peptides are ANP agonists.

The new cyclopeptides represent partial sequences, interlinked discontinuously

Partial sequences, modified partial sequences and analogues of the so-called "atrial natriuretic

Factor ", ANF, or" atrial natriuretic peptide ", ANP.

ANP is mainly found in the muscle cells of the

Cardiac foreheads synthesized, also stored there as prohormone and released by the mechanical stimulus of increased wall tension. It has a vasodilatory, hypotensive, diuretic and saluretic effect, increases glomerular filtration, reduces plasma volume and increases hematocrit, and lowers it

 Plasma renin activity and the plasma aldosterone level, acts spasmolytically on the smooth muscles of the

Intestinal and broncholytic. The effect is mediated via specific receptors.

The in this description and the claims

Abbreviations used follow the recommendations of IUPAC-IUB Joint Commission of Biochemical Nomenclature (Eur. J. Biochem. 138, 9-37 (1984). Some others

Abbreviations have been added. Some of these abbreviations are listed below: Aand ω-aminoundecanoic acid

 Abut γ-aminobutyric acid

 Aoc ω-amino octanoic acid

 Apen δ-aminopentanoic acid

 Aca ε-aminocaproic acid

 Aib α-aminoisobutyric acid

 Ala alanine

ßAla ß-alanine

 Arg arginine

 Asp aspartic acid

 Azt

 Bum tert-butyloxymethyl

 BOC tert-butyloxycarbonyl

 Btu 3-amino-1-carboxyrnethyl-pyrrolidin-2-one

Bzl benzyl

 Bz benzoyl

 Cha cyclohexylalanine

 Cle cycloleucine

 Clg 3-amino-1-carboxymethyl-hexahydro-azepin-2-one

 Ctr Citrulline

 Dap 2,3-L-diaminopropionic acid

 DMF N, N-dimethylformamide

 DPPA diphenylphosphoryl azide

 DCC dicyclohexylcarbodiimide

 DIC diisopropyl carbodiimide

 Gly glycine

 His histidine

 HOBt 1-hydroxybenzotriazole

 Ile isoleucine

 Leu leucine

Lys lysine Menoc mentyloxycarbonyl

 Me methyl

 With methionine

 Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl

Nal 1-naphthylalanine

Nle CH ₃ - (CH ₂ ) ₂ -CH (NH ₂ ) -COOH

 Orn ornitine

 Phe phenylalanine

 Pmc pentamethylchromanesulfonyl

 Ser Serin

 Thc 3-amino-7-carboxy-tetrahydro-isoquinolin-1-one

Thi CH ₂ -CH (NH ₂ ) -COOH

 Tos Tosyl

Trc

 Trt trityl

 Tyr tyrosine

 Val valine

 Z benzyloxycarbonyl

The expression amino acid encompasses (unless the following text expressly states otherwise)

natural and unnatural amino acids, both of the D and the L form. The expression also includes

"α-amino acid" also α, α-disubstituted

Amino acids.

If an amino acid is given without a prefix (e.g.

Orn) this represents the L-form of the amino acid. The D-form is expressly stated (eg D-Orn). The invention relates to cyclopeptides of the general formula I with ANP agonistic activity, An-Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn (I)

 where the sequence of terms Bn to Kn is the sequence of

 Amino acid residues of the hANP

 -Arg (27) -Phe (8) -Gly (9) -Gly (10) -Arg (11) -

Met (12) -Asp (13) -Arg (14) -Ile (15) - or their spatial structural and functional equivalents and An is a spacer group that connects Bn with Kn and the spatial structure of

 influenced each molecule in that the

 Bind cyclopeptides to ANP receptors and their pharmaceutically acceptable salts.

Cyclopeptides are preferred in which the spacer group An contains an aromatic or cycloaliphatic radical in the part closest to the Bn member.

Most amino acid residues can be in the D or L form. Cyclopeptides in which the members or the majority of the members Bn, Cn, En, Fn, Gn, Hn, In and Kn are in the L-form are preferred.

The spacer group An holds the α-C atoms of the members Bn and Kn at a distance of 5 to 15 angstroms.

 (Conformations from 2D NMR measurement in aqueous solution, results as boundary conditions for molecular dynamics simulation).

An does not bind to ANP receptors, but influences the receptor binding ability and thus the pharmacological action of the cyclopeptides of the general formula I.

Spatial structural and functional equivalents of the amino acid residues of the ANP are understood to mean amino acid residues or peptide templates (both the L-form and the D-form) which have the effect that the

Bind cyclopeptides of the general formula I to ANP receptors. The previous studies have shown that e.g. the consequence (Bn to Kn) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- gives very good receptor binding values and pharmacological effects. The individual links in the sequence are remnants of similar spatial structure

and / or function replaceable, the

Receptor binding ability of the cyclopeptide is more or less affected and the degree and in some

Cases the type of pharmacological effect is changed within the known ANP-agonistic effect. The type, amount and duration of the pharmacological effect are thus varied by the individual limbs

influenceable. If more than one of the terms Bn to Kn is varied, then the previous one will settle

State of knowledge of the change in pharmacological

Properties from the changes to the corresponding

Single variations together. The following compilation shows the using structurally similar examples

Relationship between receptor binding ability and sequence of the members of the cyclopeptides of the general formula I. (test description is described below in the text: "binding to ANP receptors"). The connections marked with *) have an IC ₅₀ -

Value in the mentioned ANP receptor binding test of less than 5.10 ^-8 mol, the other compounds have a lower one

Affinity.

A *) ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

B *) ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

C ßAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asρ-D-Arg-Ile

D *) Z-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 E H-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

G *) ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

H *) ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

I ßAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

K *) ßAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 L ßAla-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Wie bereits oben erwähnt worden ist, umfaßt der Ausdruck Aminosäure natürliche und unnatürliche Aminosäuren.

As mentioned above, the term amino acid encompasses natural and unnatural amino acids.

The unnatural amino acids are expedient, unless explicitly specified otherwise, in

In relation to their molecular weight or the length of the

Side chains, on the order of natural

Amino acids.

Particularly suitable salts are those with physiologically compatible inorganic or organic acids, such as, for example, HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ , maleic acid,

Fumaric acid, citric acid, tartaric acid, acetic acid in question,

The chirality centers in the new peptides can each have R, S or R, S configurations.

The elements Bn, Fn and In correspond to the Arg (27), Arg (11) and Arg (14) of ANP or their

spatial structural and functional equivalents. Bn, Fn and In can independently of one another be α-amino acid residues with two basic side chains or preferably one basic side chain. Basic side chain here is preferably understood to mean an alkyl or cycloalkyl side chain which contains 1 to 4 (preferably 1 or 2) basic groups. Suitable basic groups are e.g. B. -NH-, = NH, -NH ₂ , -HN-C (NH) -NH ₂ ,

-C (NH) -NH ₂ . Preferably at least one of the

 basic groups of the respective side chain

 bidentate basic group. Furthermore, side chains are preferred, the first basic group of which with the

 5-carbon atom of the α-amino acid is connected or with a carbon atom which is still further from that

 Backbone of the peptide is removed. Are preferred

 Alkyl side chains with 1-6, especially 3 or 4

-(CH₂)_y-, worin x und y unabhängig voneinander 0, 1 oder 2 sind und

für Cycloalkyl mit 5 oder 6 Carbon atoms and cycloalkyl side chains - (CH ₂ ) _x -

- (CH ₂ ) _y -, where x and y are independently 0, 1 or 2 and

for cycloalkyl with 5 or 6

 Carbon atoms. The basic group is preferably at the end of the side chain.

As mentioned above, the term Cn corresponds to Phe (8) of the ANP or its structural and functional equivalents. Cn can be an a-amino acid residue with two lipophilic

 Side chains or preferably a lipophilic

 Side chain. Lipophilic side chain at this position means an alkyl side chain with 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, in particular with 1 carbon atom). This alkyl side chain can contain one or two oxy group (s) (-O-), thio group (s) (-S-) or -C (O) O group (s). This alkyl side chain carries one or two residues. These residues are independently cycloaliphatic or aromatic residues. The

Cycloaliphatic radical (preferably cycloalkyl radical) contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic radical is preferably phenyl, naphthyl, substituted (e.g. by NO ₂ , hydroxy,

Phenyl (C _1-4 ) alkyloxy or C ₁ -C ₄ alkoxy) phenyl or a 5- or 6-membered possibly also

benzo-fused aromatic heterocycle, wherein 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the others

Links C are, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl.

The elements Dn and En correspond, as mentioned, to Gly (9) and Gly (10) of the ANP or their

spatial structural and functional equivalents.

Dn and En can independently be Gly or an α-amino acid residue, which is the spatial structure of the native

Mimicking amino acid (Gly), or Dn and En together can mean an ω-amino acid residue -NH (CH ₂ ) _2-11 -CO- or a peptide template. At positions Dn and En, amino acid residues are preferably suitable, according to the statistical analyzes by Chou and Fasman

 (Biophysical Journal, Volume 26, 1979, 367-383) in

ß-turn conformations can often be found.

To emphasize are e.g. the amino acids in the

Positions i + 1 and i + 2 occur with increased frequency, especially those with a frequency from 0.06 (Table 1 of the publication mentioned).

Suitable peptide templates include those

highlight the ß-turn-imitative conformation,

The links Gn and Kn correspond, as mentioned above, to Met (12) and Ile (15) of ANP or their spatial and functional structures Equivalents. Gn and Kn can independently of one another be α-amino acid residues each with two lipophilic side chains or preferably one lipophilic side chain.

Lipophilic side chain at these positions is preferably understood to mean an alkyl side chain with 1 to 10 C atoms, preferably 1 to 6 C atoms, in particular those with at least 3 C atoms. This alkyl side chain can additionally 1 or 2 oxy group (s) (-O-) or

Thio group (s) (-S-) (such as in methionine) included. This side chain can also contain 1 to 2 alkyl radicals.

As mentioned above, the link Hn corresponds to the Asp (13) of ANP or its spatial and functional structure

Equivalents. The link acts as a spacer. Hn can be an α-amino acid residue, namely Gly or a residue which has no functional group in the side chain or -COOH and / or -CONH ₂ . The side chain is preferably an alkyl side chain with 1 to 6 (preferably 1-3) carbon atoms, which can also carry a phenyl group and / or HOOC (CH ₂ ) _1-4 or H ₂ N-CO (CH ₂ ) _1-4 -.

As described above, stands for one

Spacer group. This group can a) the group -A ₁ -A ₂ -A ₃ - b) the group -A ₄ -A ₅ - c) an amino acid residue of the formula III

-NH- (CH ₂ ) _m -CH (R) -CO- (III)

 his.

A ₁ can be Gly or an α-amino acid residue with two

Side chains or preferably a side chain. These side chains have no functional groups. Such a side chain is preferably a branched or unbranched alkyl side chain with 1-6 carbon atoms. A ₂ is a covalent bond or a

 ω-amino acid residue of formula II,

-NH- (CH ₂ ) _n -CO- (II) where n is an integer from 1 to 11 (preferably 1 to 6).

A ₃ can be an α-amino acid residue with two lipophilic

Side chains or preferably a lipophilic

Side chain. Under lipophilic side chain, an alkyl side chain with 1 to 7

C atoms (preferably 1 to 4 C atoms, in particular with 1 C atom) understood. This alkyl side chain can contain one or two oxy group (s) (-O-), thio group (s) (-S-) or -C (O) O group (s). This alkyl side chain carries one or two residues. These residues are independently cycloaliphatic or aromatic residues. The cycloaliphatic radical (preferably cycloalkyl radical) contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic radical is preferably phenyl, naphthyl, substituted (for example by NO ₂ , hydroxy, phenyl (C _1-4 ) alkyloxy or C ₁ -C ₄ alkoxy) phenyl or a 5- or

 6-membered, possibly also benzo-condensed

 aromatic heterocycle, in which two members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl , Pyrimidinyl, pyridazinyl, indolyl,

Isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl. A ₄ can be a peptide template or an ω-amino acid residue of the formula

- NH - (CH ₂ ) _n - CO - (II)

 where n is an integer from 1 to 11

 (preferably 1 to 6);

The term peptide template includes groups such as Clg, Btu, The and Trc.

A ₅ can be a covalent bond or

 an α-amino acid residue with two lipophilic

 Side chains or preferably a lipophilic side chain. Under this lipophilic side chain, an alkyl side chain with 1 to 7 C atoms (preferably 1 to 4 C atoms,

 especially understood with 1 C atom). This

 Alkyl side chain may contain one or two oxy group (s) (-O-), thio group (s) (-S-) or -C (O) O group (s). This alkyl side chain carries one or two residues. These residues are independent

from each other cycloaliphatic or aromatic radicals. The cycloaliphatic radical (preferably cycloalkyl radical) contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic radical is preferably phenyl, naphthyl, substituted (for example by NO, hydroxy, phenyl (C _1-4 ) alkyloxy or

C ₁ -C ₄ alkoxy) phenyl or a 5- or

 6-membered optionally benzo-fused aromatic heterocycle, in which 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl,

 Imidazolyl, pyrazolyl, pyridyl, pyrazinyl,

 Pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl,

Morpholinyl. An can also be an amino acid residue of the formula III -NH- (CH ₂ ) _m -CH (R) -CO- (III), where m is an integer from 1 to 11 and

R NHX, OX, SX, NXY, -NH (H) -C (O) -CH ₂ -X ¹ ,

-N (H) -C (O) -CH ₂ -OX ¹ ,

-N (H) -C (O) -X ¹ ,

-N (H) -C (O) -CH = CH-X ¹ or

-N (H) -C (O) -O-CH ₂ -X ¹ , wherein

X represents hydrogen, an unsubstituted or substituted benzoyl radical, one

 unsubstituted or substituted

 Cyclohexyloxycarbonyl, one

 unsubstituted or substituted

 Benzyloxycarbonylrest, a 2-, 3- or

 4-pyridylmethyloxycarbonyl radical or a tosyl radical,

 Y represents a C1 to C14 alkyl radical or aryl (C1 to C14 alkyl) radical and

X ¹ (α) phenyl, (ß) by 1, 2 or 3

 Substituent (s): halogen, trifluoromethyl or nitro) substituted phenyl, (γ) naphthyl, (δ) benzo [b] thienyl, (ε) pyridyl or (η) pyrazinyl.

An amino acid residue of the formula is preferred

III, where m is 1, 2, 3 or 4 and R is -NHX,

-NXY, -

-NH (H) -C (O) -CH ₂ -X ¹ ,

-N (H) -C (O) -CH ₂ -OX ¹ ,

-N (H) -C (O) -X ¹ ,

-N (H) -C (O) -CH = CH-X ¹ or

-N (H) -C (O) -O-CH ₂ -X ¹ . Preferred cyclopeptides of the general formula are those in which

Bn, Fn and In are independently Arg, D-Arg, Lys, D-Lys, Orn, D-Orn, Homo-Arg, D-Homo-Arg, Dap, D-Dap or 4-Amino-Phe, preferably Arg , D-Arg, Lys, D-Lys or Orn;

Cn Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha, Ser (Bzl), D-Ser (Bzl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr (Bzl), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or D-Glu (Bzl), preferably Phe, Cha, Tyr, Nal, Tyr (Bzl) or (4-NO ₂ ) -Phe;

Dn and En are independently Ala, Gly, Pro, Ser, Asn, Lys, Asp or Thr or their D-form, preferably Dn D-Ala, Gly, Pro, D-Pro, Ser or D-Ser;

En is Gly, Asp or Asn; or

Dn and En together are an ω-amino acid residue of the formula -NH- (CH ₂ ) _2-5 -CO- or a peptide template, preferably Btu, Clg, The or Trc or their

D forms, especially D-Btu;

Gn and Kn are independently Ile, D-Ile, Met, D-Met, Nle, D-Nle, Leu, D-Leu, Val or D-Val; preferably Ile, Met, Nle or Leu;

Hn HOOC- (CH ₂ ) _1-4 -CH (NH -) - CO-, their D-forms,

Is Gly, Ala, D-Ala, Asn, D-Asn, Phe or D-Phe, preferably Asp, Glu or Gly;

At a) At the group -A ₁ - A ₂ - A ₃ -, in which

A _{1 is} Ala, Gly, Phe, Val, Ile, Leu or Nle or their D-form, preferably Gly, Ala or D-Ala;

A _{2 is} an ω-amino acid residue of formula II, wherein n is 2, 3 or 5;

A ₃ Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha,

Ser (Bzl), D-Ser (Bzl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr (Bzl), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp Is (Bzl), His or D-His, preferably Phe, Tyr, Cha, Nal or (4-NO ₂ ) Phe; or b) the group is -A ₄ - A ₅ -, wherein A _{4 is} a

 ω-amino acid residue of formula II, wherein n is 2, 3 or 5;

A ₅ Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha,

 Ser (Bzl), D-Ser (Bzl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr (Bzl), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or

Is D-Glu (Bzl), preferably Phe, Tyr, Cha, Nal or (4-NO ₂ ) -Phe; or c) an amino acid residue of the formula III, in which m 1,

2, 3 or 4 and R is as defined in claim 8, wherein X represents hydrogen, an unsubstituted or substituted by chlorine, methoxy or (C1 to C3) alkyl benzoyl radical, cyclohexyloxy or menthyloxycarbonyl radical, one

 unsubstituted or substituted by methoxy, nitro, trifluoromethyl or cyano

 Benzyloxycarbonylrest, preferably represents benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- or 4-trifluoromethylbenzylcarbonyl or 4-nitrobenzyloxycarbonyl, in particular benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or 2- or

 4-trifluoromethylbenzyloxycarbonyl,

Y represents a C1 to C14 alkyl radical or (C1 to C14 alkyl) phenyl radical, preferably benzyl or phenylethyl;

and

X ¹ for phenyl or mono- or

 di-substituted phenyl, 2-pyridyl,

 2-pyrazinyl, 3-benzo [b] thienyl, or

 2-naphthyl, especially those in which

At the group -A ₁ - A ₂ - A ₃ - is in which

A _{1 is} Gly,

A ₂ Aca, ßAla, Apen, Abut, Gly, or a covalent

Bond is, and

A _{3 is} Phe, Phe (4-NO ₂ ), Tyr or Tyr (Bzl); or

To the group - A ₄ - A ₅ - is where

A ₄ ßAla, Aca, The, Aund, Btu or D-Btu is, and

A _{5 is} a covalent bond, Phe, D-Phe,

Is Phe (4-NO ₂ ), Tyr, Tyr (Bzl) or Cha; or An amino acid residue of formula III

-NH- (CH ₂ ) _n -CH (R) -CO-, wherein m is 1 or 4 and R is the group -NHX, where X is H, Z, Bz, Menoc, (4-NO ₂ ) Z, Tos or An X ² - Lys-, wherein

X ^{2 is} one of the following groups

To be emphasized are cyclopeptides of the general formula la A ₁ -A ₂ -A ₃ -Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn

 and their salts, in which

A ₂ Aund,

 Aca,

 ß-Ala,

 Apen,

 Abut or

 Is Gly or a covalent bond;

A ₃ Phe,

Phe (4-NO ₂ ),

 Cha,

 Tyr or

 Is Tyr (Bzl);

Bn is Arg;

Cn Phe,

 Cha,

 Is Tyr or Tyr (Bzl);

Dn D-Ala,

 Is Pro or D-Pro;

En is Gly; or

Dn and En together ß-Ala,

 Abut,

 Aoc,

 L-Clg,

 Are L-Btu or D-Btu;

Fn Arg or

 Lys is;

Gn Ile,

 Mead,

 Aib or Nle is;

Hn Asp or

 Aib is;

In Arg is;

Kn Ile is and A _{1 is} Gly. Cyclopeptides or their salts, in which

A _{2 is} an ω-aminoalkanoic acid residue of the formula

Is -NH- (CH ₂ ) _2-4 -CO-;

A _{3 is} Phe, Tyr, Cha, Nal or 4-NO ₂ -Phe;

 Bn, Fn and In independently of one another Arg, D-Arg,

 Are Lys, D-Lys, Orn or Ctr;

 Cn is Phe, Cha, Tyr, Nal or Tyr (Bzl);

 Dn is D-Ala, Gly, Phe or D-Phe;

 En is Gly or Ala; or

 Dn and En together are D-Btu;

 Gn and Kn independently of each other Ile, Met, Nle or

 Are leu;

 Hn is Asp, Glu or Gly; and

A _{1 is} Gly, Ala or D-Ala; especially those in which

A ₂ ß-Ala,

 Apen or,

 Abut is;

A ₃ Phe,

Phe (4-NO ₂ ),

 Cha or,

 Tyr is;

Bn is Arg;

Cn Phe,

 Cha,

 Tyr or

Is Tyr (Bzl); Dn is D-Ala;

En is Gly; or

Dn and En together

 D-Btu are;

Fn Arg or

 Lys is;

Gn Ile,

 Mead or

 Nle is;

Hn Asp;

In Arg is;

Kn Ile is; and

A _{1 is} Gly.

Preferred compounds according to the invention are:

1. Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

2. Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

4. ßAla-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly

5. ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

3. Aca-Phe-Arg-Phe-D-Ala-Gly-Lys-Ile-Asρ-Arg-Ile-Gly

4. ßAla-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly

5. ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

6. Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

7. ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Met-Asp-Arg-Ile-Gly

8. ßAla-Cha-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 9th

ßAla-Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 10th

ßAla-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Eq

11. ßAla-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

12th

ßAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

14. Aca-Phe-Arg-Phe-Abut-Arg-Ile-Asp-Arg-Ile-Gly

13. Aca-Phe-Arg-Phe-ßAla-Arg-Ile-Asp-Arg-Ile-Gly

14. Aca-Phe-Arg-Phe-Abut-Arg-Ile-Asp-Arg-Ile-Gly

15. Apen-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

16. Abut-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

17. Gly-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 18. βAla-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 19. Aca-Arg-Phe-D-Ala-Gly-Arg-Ile-Asρ-Arg-Ile-Gly

 20. Aund-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 21. Aca-Phe-Arg-Phe-Aoc-Arg-Ile-Asp-Arg-Ile-Gly

22. ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Aib-Asp-Arg-Ile-Gly

23. βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Aib-Arg-Ile-Gly

 24 βAla-Phe-Arg-Phe-L-Btu-Arg-Ile-Asp-Arg-rie-Gly

25. ßAla-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly

25. ßAla-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly

26. βAla-Phe-Arg-Phe-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly

27. ßAla-Phe-Arg-Phe-D-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 28. Tyr-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

29. Tyr (Bzl) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 30. Phe-Arg-Tyr-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

31. Phe-Arg-Tyr (Bzl) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 32. βAla-Phe-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-Gly

33. βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Nle-Asp-Arg-Ile-Gly

as well as their salts. Of particular note are cyclopeptides of the general formula Ib A ₄ -A ₅ -Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn

 and their salts, in which

A ₄ Aund,

 Aca,

 ß-Ala,

 Clg, The, Btu or D-Btu is

A ₅ Phe, D-Phe,

Phe (4-NO ₂ ),

 Cha,

 Tyr,

 Is Tyr (Bzl) or a covalent bond;

Bn Arg,

 D-Arg,

 Ctr,

Is Lys or a covalent bond;

Cn Phe,

 Cha,

 Ser (Bzl) or

 Is Tyr (Me);

Dn D-Ala,

 Gly or

 Azt is;

En is Gly;

Fn Arg or

 Lys is;

Gn Ile, D-Ile,

 Mead or

 Nle is;

Hn Asp, D-Asp

 Is Gly or a covalent bond;

Is in Arg or D-Arg; and

Kn Ile is.

Cyclopeptides or their salts, in which

A _{4 is} an ω-aminoalkanoic acid residue of the formula

-NH- (CH ₂ ) _2-4 -CO-, or, if A _{5 is} a covalent bond,

 Is Clg, Thc, Btu or D-Btu;

A _{5 is} Phe, Tyr, Cha, Nal or 4-NO ₂ -Phe; Bn, Fn and In independently of one another Arg, D-Arg,

Are Lys, D-Lys, Orn or Ctr;

 Cn is Phe, Cha, Tyr, Nal or Tyr (Bzl);

 Dn is D-Ala, Gly, Phe or D-Phe;

 En is Gly or Ala; or

 Dn and En together are D-Btu;

 Gn and Kn independently of each other Ile, Met, Nle or

Are leu; and

 Hn is Asp, Glu or Gly; especially those in which

A ₄ ß-Ala,

 Apen or,

Is abut, or if A _{5 is} a covalent bond,

Is Clg, The, Btu or D-Btu; A ₅ Phe,

Phe (4-NO ₂ ),

 Cha or,

 Tyr is; or

Bn is Arg;

Cn Phe,

 Cha,

 Tyr or

 Is Tyr (Bzl);

Dn is D-Ala; En is Gly; or

Dn and En together

 D-Btu are;

Fn Arg or

 Lys is;

Gn Ile,

 Mead or

 Nle is;

Hn Asp;

In Arg is; and

Kn Ile is.

Preferred compounds according to the invention are:

1. ßAla-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

2. Aca-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

3. ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

5. ßAla-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

4. Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

5. ßAla-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

6. ßAla-Phe-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asρ-Arg-Ile

 7. Aca-Phe-Lys-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 8. Aca-Phe-Lys-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-Ile

 9. Aca-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 10. Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 11. Aca-Cha-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 12. ßAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 13. ßAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile

14. ßAla-Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 15. ßAla-Phe-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

16. Clg-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

16. Clg-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

17. ßAla-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

18. ßAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 19. βAla-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 20. Thc-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 21. ßAla-Phe-Ctr-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

22. Thc-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 23. Clg-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

24. Aund-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

25. Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 26. Aca-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

27. Aca-Arg-Ser (Bzl)-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

27. Aca-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 28. Aca-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

29. βAla-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

 30. Aca-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

 31. βAla-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

32. βAla-Phe-Gly-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

33. Aca-Phe-Gly-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 34. βAla-Gly-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 35. Aca-Gly-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 36. βAla-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

38. Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-I le37. Aca-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

38. Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

 39. D-Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 40. βAla-Arg-Phe-D-Ala-Gly-Arg-Ile-Arg-Ile

 41. pAca-Arg-Phe-D-Ala-Gly-Arg-Ile-Arg-Ile

42. βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Btu

 43. Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Gly-Arg-Ile

44. Aca-Phe-Arg-Tyr (Me) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

45. Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-D-Ile-Asp-Arg-Ile

46. Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-D-Asp-Arg-Ile

47. Aca-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

49. Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile48. Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

49. Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

50 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

51. βAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

 52. Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

53. βAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 54. βAla-Phe-Arg-Cha-Azt-Gly-Arg-Ile-Asp-Arg-Ile

 55. βAla-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 56. Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

sowie deren Salze . Hervorzuheben sind Cyclopeptide der allgemeinen Formel I, und ihre Salze, worin 57. Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

as well as their salts. To be emphasized are cyclopeptides of the general formula I, and their salts, in which

To H-Lys

 Z-Lys

 Bz-Lys

 Menoc-Lys,

(4-NO ₂ ) Z-Lys

 Bz-D-Lys

 Tos-Lys

 H-Dap or

 Z-Dap is;

Bn Arg,

 Lys,

 Phe or

 Orn is;

Cn Phe,

 Cha or

Ser (Bzl) is;

Dn is D-Ala;

En is Gly; or

Dn and En together

 L-Clg or

 Are D-Clg;

Fn Arg or

 Lys is;

Gn ile or

 Nle is;

Hn Asp;

In Arg is; and

Kn Ile is.

Cyclopeptides or their salts, in which

 An aminoalkanoic acid residue of the formula

-NH- (CH ₂ ) _n -CH (R) -CO-, wherein

 n is 1 or 4, R is NHX or NXY, X is benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2- or 4-trifluoromethylbenzyloxycarbonyl, cyclohexyloxycarbonyl or menthyloxyearbonyl and Y is benzyl or phenylethyl;

 Bn, Fn and In are independently Arg, D-Arg, Lys, D-Lys, Orn or Ctr;

Cn is Phe, Cha, Tyr, Nal, Tyr (Bzl) or 4-NO ₂ -Phe; Dn is D-Ala, Gly, Phe or D-Phe;

 En is Gly, Ala or Phe; or

 Dn and En together are D-Btu, L-Clg or D-Clg;

Gn and Kn independently of each other Ile, Met, Nle or

Are leu; and

 Hn is Asp, Glu or Gly; especially those in which

To H-Lys

 Z-Lys

 Bz-Lys

 Menoc-Lys,

(4-NO ₂ ) Z-Lys

 Bz-D-Lys

 Tos-Lys

 H-Dap or

 Z-Dap is;

Bn is Arg, Lys, Orn or Phe;

Cn Phe,

 Cha or

 Ser (Bzl) is;

Dn is D-Ala;

En is Gly; or

Dn and En together

Are L-Clg or D-Clg; Fn Arg or

 Lys is;

Gn ile or

 Nle is;

Hn Asp;

In Arg is; and

Kn Ile is.

Preferred compounds according to the invention are: 1. H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

2. Z-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

3rd Z-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 4th Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 5. Z-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

7. Menoc-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

6. Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

7. Menoc-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

8. Menoc-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 9. H-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 10. Z-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 11. Z-Lys-Phe-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

12. (4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 13. Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 14. H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

15. H-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 16. Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 17. Bz-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

18. Bz-D-Lys-Arg-Ser(Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

18. Bz-D-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 19. Tos-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 20. H-Lys-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile

 21. Z-Lys-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile

 22. Z-Lys-Arg-Cha-L-Clg-Arg-Ile-Asp-Arg-Ile

23. Z-Lys-Arg-Cha-D-Clg-Arg-Ile-Asp-Arg-Ile

24th H-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 25. Z-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

sowie deren Salze .

as well as their salts.

Of particular note are cyclopeptides of the general formula I and their salts, in which

As defined above,

Bn Arg,

 Lys,

 Phe or

 Orn is;

Cn Phe,

 Cha or

 Ser (Bzl) is;

Dn is D-Ala;

En is Gly; or

Dn and En together

 L-Clg or

 Are D-Clg;

Fn Arg or

 Lys is;

Gn ile or

 Nle is;

Hn Asp;

In Arg is; and

Kn Ile is.

Cyclopeptides or their salts, in which An aminoalkanoic acid residue of the formula

-NH- (CH ₂ ) _n -CH (R) -CO-, wherein

 n is 1 or 4,

R -NH (H) -C (O) -CH ₂ -X ¹

-N (H) -C (O) -OH ₂ -OX ¹

-N (H) -C (O) -X ¹

-N (H) -C (O) -CH = CH-X ¹ or

-N (H) -C (O) -O-CH ₂ -X ¹ ,

wherein X ¹ (a) phenyl, (b) by 1 or 2

Substituted substituted phenyl, (c) 1- or

Is 2-naphthyl, (d) 3-benzo [b] thienyl, (e) 2-pyridyl or (f) 2-pyrazinyl;

 Bn, Fn and In independently of one another Arg, D-Arg,

Are Lys, D-Lys, Orn or Ctr;

Cn Phe, Cha, Tyr, Nal, Tyr (Bzl) or 4-NO ₂ -Phe

 is;

 Dn is D-Ala, Gly, Phe or D-Phe;

 En is Gly, Ala or Phe; or

 Dn and En together are D-Btu, L-Clg or D-Clg; Gn and Kn independently of each other Ile, Met, Nie or

Are leu; and

 Hn is Asp, Glu or Gly; especially those in which

An is -NH- (CH ₂ ) ₄ -CH (R) -CO-, wherein

 R is as defined above and

-B _n -C _n -D _n -E _n -F _n -G _n -H _n -I _n -K _n - die

 Chain -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- is, with special attention to the examples.

The compounds of the invention are ANP agonists. Like natural ANP, they show - specific and affine binding to ANP receptors - diuretic and saluretic properties

- hypotensive effect - hematocrit increase

- Increasing the plasma level of cyclic GMP (GMP: probably the intracellular messenger ("second messenger"), which can be detected in plasma after ANP administration.)

 - Increase in glomerular filtration

- vasodilatory effect

- broncholytic effect

 - spasmolytic effect on smooth muscles,

 especially on the intestine.

These properties of the compounds according to the invention are tested in detail as follows: Binding to ANP receptors

 Binding to ANP receptors of zona glomerulosa cells from bovine adrenal glands is carried out according to the method of Bürgisser et al. (Biochem. Biophys. Res. Commun. 133, 1201 (1985)), modified after Bürgisser (2nd World Congress on Biologically Active Atrial

 Peptides, May 16-21, New York Am. Soc. Hypertens., Abstr. B181, P. 209 (1987)) with a commercially available kit from ANAWA, Wangen, Switzerland. - lowering blood pressure, diuretic / saluretic effect.

 Hematocrit increase, cyclo-GMP increase

 The examinations are anesthetized

(Nembutal ^R ) spontaneously hypertensive rats

(Ivanovas) performed. The trachea is cannulated. Blood pressure is recorded from the carotid artery via a pressure-voltage converter (Statham) on a recorder (Watanabe multicorder). The heart rate is calculated from the number of pulse waves per unit of time calculated. The substance is administered through a cannulated jugular vein. The bladder is cannulated by a small abdominal incision and the urine is collected. The urine volume is determined gravimetrically. Sodium and potassium

 measured by flame photometry, chloride through

 Electrotitration. The hematocrit is measured from the arterial blood. Cyclic GMP is obtained from arterial blood using a commercially available radioimmunoassay (IBL, Hamburg)

 certainly. - Influence on glomerular filtration

 The glomerular filtration rate is on

 anesthetized dog by determining the

 Inulin clearance measured according to standard procedures, Führ et al. (Klin. Wschr. 33, 729 (1955)). - vascular relaxation

 The vasodilatory effect in analogy to ANP is determined using a modified method by Faison et al. (Eur. J. Pharmacol. 102, 169 (1984)). The rabbit breast aorta is characterized by a

 contracted supramaximal serotonin concentration. 15 minutes after adding the test substance, the serotonin contraction is compared to

Solvent control measured. The EC _{50 is} determined graphically from several doses. - Broncholytic effect

 According to the method of Konzett and Rössler (Arch.

exper. Path. Pharmacol. 195, 71 (1940)) the antagonization of histamine bronchospasm after iv administration of the test substance is examined. - Spasmolytic effect on the chicken rectum

 According to the method of Currie et al. (Science,

 221/4605, 71 (1983)) the spasmolytic effect against a carbachol contraction on the chicken rectum is determined.

The compounds according to the invention can be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, preferably by

Iontophoresis or known enhancers promoted, and take place orally. In the whole animal of different species, the doses are a significant reduction in blood pressure (> 20 mmHg) and / or diuresis (+ 300%) or saluresis

(+ 300%) and an increase in hematocrit (+ 3%) and cyclic GMP (+ 200%) between

1 μg / kg and 50 mg / kg. The doses for a broncholytic effect on guinea pigs are the same

Orders of magnitude. Binding to the receptors of the ANP in

Zona glomerulosa cells from bovine adrenal glands are carried out with an IC ₅₀ between 1.10 ^-10 and 1.10 ^-5 mol / l.

Vascular relaxing effects on rabbit aortic rings occur in vitro with an EC ₅₀ between 1.10 ^-9 and

1.10 ^{- 4} mol / l. The concentrations for a spasmolytic effect on the chicken rectum are in the same

Orders of magnitude.

Since the receptor binding of the individual compounds according to the invention and that of ANP correlates well with the biological effects in terms of potency, the identity of the mechanism of action is natural between the

occurring peptides and those described here Connections. Thus, further biological properties described for the natural peptide ANP, which are not described in detail here, can also be expected from the compounds according to the invention.

The orders of magnitude of the effects of the compounds according to the invention are comparable to those of ANP. The main advantage of the compounds according to the invention is their significantly smaller molecular size. From the prior art it could not be concluded that the connections with so much less

Molecular size data of activity have a satisfactory size. Due to the smaller molecular size, the synthesis of the compounds according to the invention is considerably simpler and therefore cheaper than the synthesis of ANP or of ANP derivatives with large molecular weights which are similar to that of ANP. The bioavailability of the compounds according to the invention (in particular when transdermally administered) is considerably greater than in the case of ANP and ANP-like

Derivatives. In contrast to ANP, the compounds according to the invention contain no disulfide bridges, which improves their metabolic stability compared to ANP and ANP-like derivatives.

The following compounds are particularly emphasized because their ANP receptor binding values (test description see above "binding to ANP receptors") IC _{50 are} less than 5 × 10 ^-8 mol.

Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Aca-Phe-Arg-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-Ile-Gly

 ßAla-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Met-Asρ-Arg-Ile-Gly

ßAla-Phe(4-NO2)-Arg-Phe-D-Ala-Gly-Arg-I le-Asp-Arg-Ile-Gly

ßAla-Phe(4-NO2)-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Cha-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-I le-Asp-Arg-Ile-Gly

ßAla-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Tyr(Bzl)-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Apen-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Abut-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Gly-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Phe-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Phe-D-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Tyr-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Tyr (Bzl) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Phe-Arg-Tyr (Bzl) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Phe-Arg-Tyr-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Phe-Arg-Tyr (Bzl) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Nle-Asp-Arg-Ile-Gly

 ßAla-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Aca-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

ßAla-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

ßAla-Phe-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Aca-Phe-Lys-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

 Aca-Phe-Lys-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-I le

 Aca-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Aca-Cha-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 ßAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 ßAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile

ßAla-Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 ßAla-Phe-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

ßAla-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

ßAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-

 ßAla-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

 ßAla-Phe-Ctr-Cha-D-Ala-Gly-Arg-I le-Asp-Arg-Ile

 Thc-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Aund-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Aca-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-I le

Aca-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

D-Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Gly-Arg-Ile

Aca-Phe-Arg-Tyr (Me) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-D-Ile-Asp-Arg-Ile

Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-I le-D-Asp-Arg-I le

Aca-Phe-D-Arg-Phe-D-Ala-Gly-Arg-I le-Asp-Arg-Ile

ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

ßAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Z-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Z-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-I le

 Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Z-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Menoc-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Menoc-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

 H-Lys-Lys-Cha-D-Ala-Gly-Arg-I le-Asp-Arg-I le

 Z-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

(4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-I le

 Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

H-Lys-Arg-Ser(Bzl)-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

H-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Bz-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Bz-D-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Tos-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 H-Lys-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile

Z-Lys-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile

Z-Lys-Arg-Cha-L-Clg-Arg-Ile-Asp-Arg-Ile

Z-Lys-Arg-Cha-D-Clg-Arg-Ile-Asp-Arg-Ile

Z-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

(4-NO₂) Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile(4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile

(4-NO ₂ ) Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

X²-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-lle

X ² -Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-lle

Aufgrund des Wirkungsspektrums können die

Due to the spectrum of effects, the

Compounds according to the invention as antihypertensives, as hypotensives, as diuretics, to promote the

Blood circulation (vasodilatory effect), e.g. at

vascular insufficiency and for the treatment of

Heart failure, coronary insufficiency, cerebrovascular insufficiency, kidney insufficiency, acute kidney failure as well as with edema of any genesis, e.g. Brain edema, also in cirrhosis of the liver, also as spasmolytics for everyone

smooth muscular organs, especially gastrointestinal tract including gallbladder as well as urinary organs and as broncholytics.

They can also be used to diagnose the listed

Disease patterns and for examining the listed organ systems can be used. In addition, they can be used as tools for production and cleaning

 (Affinity chromatography) of antibodies or

Receptor preparations as well as in immunological

Test methods (e.g. RIA, ELISA) and receptor binding tests (e.g. radioreceptor assay) are used as specific and selective ligands.

The invention therefore also relates to the use of the compounds of the general formula I as medicinal products and pharmaceutical preparations which contain these compounds. Use in humans is preferred.

For parenteral administration, the compounds according to the invention may be used with the substances customary for this, such as solubilizers, emulsifiers or others

Excipients in solution, suspension or emulsion

 brought. Examples of solvents are in question: water, physiological saline or alcohols, e.g.

Ethanol, propanediol or glycerin, sugar solutions such as glucose or mannitol solutions or a mixture of different solvents. The compounds can also be applied by implants, for example made of polylactide, polyglycolide or polyhydroxybutyric acid. Other options for application are intranasal, inhalation

Application, (piezo device, dosing aerosol,

Powder inhaler), transdermal application

(Plaster preparation, cream, ointment, gel, passive

Patches, the effect of "enhancers" for penetration and / or an electric field

(Iontophoresis) can be strengthened), the oral

Application (tablets, capsules, coated tablets, etc.).

The invention also relates to the use of

Compounds of the general formula I as components and intermediates in the above-described biochemical, biotechnical and immunological processes (generation of antibodies, affinity chromatography, RIA, ELISA, radioreceptor assay).

The compounds according to the invention can be prepared by generally known methods in peptide chemistry. Such processes are described in Houben-Weyl, Methods of Organic Chemistry Vol 15/2. Production after solid phase peptide synthesis (e.g.

G.Barany, R.B. Merrifield in The Peptides-Analysis,

Synthesis, Biology, Vol.2, 2-284 (1980), Academic Press, New York or R.C. Sheppard, Int.J.Pept.Prot.Res.21, 118 (1983)) or equivalent known methods

manufactured. As amino protecting groups, the in

Houben-Weyl, Methods of Organic Chemistry Vol 15/1 used. To be favoured

Urethane protecting groups such as the

Fluorenylmethoxycarbonyl- or die

tert-Butyloxycarbonylgruppe applied. To prevent side reactions are usually possible

existing groups in the side chains of the amino acids through suitable protective groups (see e.g. Houben-Weyl Bd 15/1 or TWGreene, Protective Groups in Organic

Synthesis) additionally protected. Arg (NO ₂ ), Arg (di-Z), Arg (Pmc), Arg (Mtr), Tyr (tBu),

Tyr (Bzl), Tyr (2,6-Di-Cl-Bzl), Ser (tBu), Ser (Bzl),

Asp (tBu), Asp (Bzl), Glu (tBu), Glu (Bzl), His (Trt),

His (Bum), Lys (Boc), Lys (Z), Z-Lys, Orn (Boc), Dap (Boc), Homo-Arg (Mtr), Homo-Arg (Pmc), Homo-Arg (NO ₂ ) .

Known resins are available for the synthesis of the compounds of the general formula I after the solid phase synthesis

Suitable for polystyrene, polyacrylamide and polyether. For the synthesis of cyclopeptides it is necessary to use anchor groups which give peptide carboxylic acids during the cleavage. It is particularly advantageous to use anchor groups in which the cleavage takes place under conditions which are so mild that any side chain protection groups which may be present are retained. When using the Fmoc strategy, such anchor groups are: the 2-methoxy-4-alkoxybenzyl alcohol group (M. Mergler et. Al., Proceedings of the 10th

American Peptide Symposium 1987, St.Louis, p.259

G.R. Marshall, ed Escom, Leiden (1988), the

Hydroxycrotonoylamidomethyl group (H.Kunz, B.Dombo,

Appl. Chem. Int. Ed. Engl. 27,711 (1988)) or the

Trialkoxybenzhydryl alcohol group (H.Rink, P. Sieber, Peptides 1988, p.139, G. Jung, E. Bayer Eds., W.deGruyter, Berlin 1989).

The amino protecting group is split off in the case of the Boc group with trifluoroacetic acid in dichloromethane or in the case of the Fmoc group preferably with organic bases, especially amines such as piperidine or morpholine in DMF or N-methylpyrrolidone (NMP). Usual concentrations are 20 to 50% of the base in the solvent

Response times are between 10 and 120 minutes.

Splitting in two steps is preferred

carried out, the first reaction time about 3

Minutes. The resin is then washed briefly with solvent. This is followed by a further cleavage with 20% piperidine in DMF, after which the solution is filtered off with suction and the resin carefully

Solvent is washed. Preferred solvents for these washing steps are DMF, NMP, dichloromethane, trichloromethane, methanol, ethanol, isopropanol, water and tetrahydrofuran. After the piperidine has been completely removed, the Fmoc amino acid required for the next coupling is coupled. This cycle will

run through one after the other until the desired one

Resin-bound peptide has emerged.

The methods known in peptide chemistry (see Houben-Weyl, Methods of Organic Chemistry Vol 15/2) can be used for coupling. Carbodiimides, such as e.g. Dicyclohexylcarbodiimide,

Diisopropyl carbodiimide, ethyl (3-dimethylaminopropyl) carbodiimide or O-benzotriazol-1-yl-tetramethyl-uronium hexafluorophosphate or tetrafluoroborate (R. Knorr et al., THL 30, 1927 (1989)) or benzotriazol-1-yl-oxy- tris (dimethylamino) phosphonium hexafluorophosphate (B. Castro et al., THL 1975, 1219). By adding

1-hydroxybenzotriazole (HOBt) or

 3-Hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) can optionally suppress racemization or increase the reaction rate. The

Amino acids Asn and Gin are preferably coupled in the form of their N-protected p-nitrophenyl esters. The Couplings are usually made with a 2- to 5-fold excess of N-protected amino acid and

Coupling reagent in solvents such as dichloromethane, dimethylformamide, N-methylpyrrolidone (NMP) or mixtures of these carried out. The course of the

Coupling reaction is by the Kaiser test (E. Kaiser et al., Anal. Biochem. 34, 595 (1970) or by the

TNBS test tracked. If an incomplete acylation is found, the coupling is carried out until

Completeness repeated. The solid phase synthesis can be done manually as well as automatically with the help of a

Peptide synthesizers are done.

The linear peptides thus synthesized are

then cyclized by suitable methods known in the literature. Cyclization reagents that can be used for coupling the amino acids or also pentafluorophenyl esters / DMAP or

Diphenylphosphoryl azide (DPPA) find application.

For the synthesis of the compounds of general formula I, the solid phase synthesis according to the

Fmoc strategy using the

2-methoxybenzyloxybenzyl ester anchor preferred. The DCC / HOBt, DIC / HOBt or TBTU methods are used as coupling methods to build up the sequences

prefers. After building up the sequences on the resin, the N-terminal Fmoc group is cleaved as usual, the resin is washed thoroughly with dichloromethane after removal of the piperidine and then with a 1% solution of trifluoroacetic acid in order to cleave the peptide

Treated dichloromethane. The remain

Side chain protecting groups of the peptides obtained. After the solvent has been distilled off, the peptides with a cyclization reagent are preferred Diphenylphosphoryl azide, to the corresponding

Cyclopeptides implemented. Subsequent side chain protecting groups are then removed by appropriate cleavage reagents. Trifluoroacetic acid / scavenger mixtures are preferred. Substances such as e.g. Anisole, thioanisole, cresol, thiocresol, ethanedithiol, water or the like and mixtures of these scavengers are preferably used. The peptides are then processed and purified using the methods customary in peptide chemistry.

The crude products obtained are purified by means of gel chromatography, e.g. on Sephadex G25 (MR <1400) or G15 (MR <1400) with 1% or 5% acetic acid. If necessary, further purification is carried out using preparative RP-HPLC with methanol or

Acetonitrile-water gradient with the addition of 1 to 2% trifluoroacetic acid.

Cation exchangers can also be used for cleaning

Sephadex or polystyrene base can be used.

The cleaning is preferably carried out by reversed phase HPLC using water / acetonitrile gradients with the addition of

0.1 to 0.2% trifluoroacetic acid.

The compounds of general formula I are checked for purity by RP-HPLC. It becomes one at a time

Amino acid analysis on the ion exchanger (LKB) and on

Gas chromatographs carried out on a chiral column for additional racemization control. In addition, 13C NMR spectra (Bruker 400 MHz) as well FAB mass spectra (Finnigan MAT 90) recorded. The sequence is determined using

Gas phase sequencing after tryptic cleavage.

The following examples illustrate the synthesis of the compounds according to the invention, without the invention being restricted thereto.

Example 1 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-I le-Asp-Arg-I le-Gly

 The peptide synthesis was carried out with an ACT200 peptide synthesizer from Advanced ChemTech using the Fmoc strategy using a modified one

 Control program. The 50 ml shaking reactor was charged with 1 g of 2-methoxybenzyl ester resin from Bachem, Switzerland, which was loaded with 0.5 mmol of Fmoc-glycine. The following amino acid derivatives were used: Fmoc-Ile-OH,

 Fmoc-Arg (Mtr) -OH, Fmoc-Asp (tBu) -OH, Fmoc-Gly-OH,

 Fmoc-D-Ala-OH, Fmoc-Phe-OH and Fmoc-ßAla-OH. The

 Couplings were made using 3

 Equivalents of Fmoc-amino acid, 1-hydroxybenzotriazole and dicyclohexylcarbodiimide were carried out (coupling time 40 minutes). After the TNBS test had been carried out, the coupling was removed with incomplete acylation

 Repeated use of the same reagents and excesses. When the acylation was complete, the next synthesis cycle was started. The Fmoc protecting groups were each cleaved with 20% piperidine in DMF (once 3 minutes, once 15 minutes).

 Between the reactions, the resin was washed 10 times with DMF. After building the linear sequence

 H-βAla-Phe-Arg (Mtr) -Phe-D-Ala-Gly-Arg (Mtr) - Ile-Asp (tBu) -Arg (Mtr) -Ile-Gly- on the polymeric support, the resin was washed thoroughly with dichloromethane and then 5 times with a maximum of 20 ml of a 1% solution of trifluoroacetic acid in dichloromethane

 Treated for 10 minutes at room temperature (until

intense purple coloring of the resin). The solutions were combined and concentrated in vacuo. The residue was triturated with ether, the ether decanted off, the peptide dried in a stream of nitrogen and in 130 ml of DMF

 was added, the pH was adjusted to about 8.5 with triethylamine, the solution was cooled to -20 ° C. and 0.2 g (0.75 mmol) of diphenylphosphoryl azide was added. It was 48 hours at -20 ° C, 48 hours at 4 ° C

 ditched. The pH was kept at 8.5 with triethylamine. Then DMF was removed in vacuo, the residue was triturated twice with ether, the ether was decanted off and the residue was removed with a

 Nitrogen stream dried. The side chain protecting groups were split off with trifluoroacetic acid / anisole (90/10) for 24 hours at room temperature. The solution was concentrated in vacuo, the residue was digested with ether and dried. The crude peptide was passed over a Dynamax C18, 3μ column (10 x 2.14 cm) using a gradient from A:

 Water / acetonitrile / trifluoroacetic acid 95/5 / 0.2 and B: same as 20/80 / 0.2 from 10% B to 80% B in 11 minutes, flow 20 ml, retention time 6.01 minutes, cleaned. After freeze-drying, an amorphous colorless powder was obtained. FAB-MS (M + H) + = 1360.5

Example 2 Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-A and-OH instead of Fmoc-βAla-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 7.45 min) was purified.

FAB-MS (M + H) + = 1473.2 Example 3 Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.00 min) was purified.

 FAB-MS (M + H) + = 1403.1

Example 4 Aca-Phe-Arg-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-Ile-Gly

Using Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH instead of Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 11 min, retention time 5.80 min). FAB-MS (M + H) + = 1374.9

Example 5 βAla-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly

Using Fmoc-D-Btu-OH instead of Fmoc-D-Ala-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.05 min) was purified.

 FAB-MS (M + H) + = 1372.7

Example 6

(4-NO2) -Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Phe (4-NO2) -OH and without

 Fmoc-βAla-OH a crude peptide was obtained as described in Example 1, which using the

described chromatography conditions (5% after 80% B in 11 min, retention time 6.45 min). FAB-MS (M + H) + = 1334.9

Example 7 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Met-Asp-Arg-Ile-Gly

 With the additional use of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.10 min) was purified.

 FAB-MS (M + H) + = 1378.8

Example 8 βAla-Cha-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Cha-OH instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1, which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 7.75 min) has been.

FAB-MS (M + H) + - 1373.0

Unter Verwendung von Fmoc-Phe(4-NO2)-OH wurde wie in Example 9 βAla-Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-I le-Gly

Using Fmoc-Phe (4-NO2) -OH, as in

 Example 1 described a crude peptide obtained which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.50 min).

 FAB-MS (M + H) + = 1406.2

Example 10 βAla-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asρ-Arg-Ile-Gly

Using Fmoc-Cha-OH and Fmoc-Phe (4-NO2) -OH instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1

 described chromatography conditions (5% after 80% B in 11 min, retention time 7.40 min).

FAB-MS (M + H) + = 1412.0

Example 11 βAla-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Tyr (tBu) -OH and Fmoc-Cha-OH instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1, which using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 6.40 min). FAB-MS (M + H) + = 1383.2

Example 12 βAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Tyr (Bzl) -OH and Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 8.50 min) was purified.

FAB-MS (M + H) + = 1473.2

Example 13 Aca-Phe-Arg-Phe-βAla-Arg-Ile-Asp-Arg-Ile-Gly

Using Fmoc-Aca-OH and Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (20% after 80% B in 10 min, retention time 4.60 min) was purified.

 FAB-MS (M + H) + = 1345.9

Example 14

Aca-Phe-Arg-Phe-Abut-Arg-Ile-Asp-Arg-Ile-Gly

Using Fmoc-Aca-OH instead of Fmoc-βAla-OH and Fmoc-Abut-OH, a crude peptide was obtained as described in Example 1, which using the

described chromatography conditions (20% after 80% B in 10 min, retention time 4.85 min). FAB-MS (M + H) + = 1373.8

Example 15 Apen-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Apen-OH instead of Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (20% after 80% B in 10 min, retention time 4.50 min) was purified.

 FAB-MS (M + H) + = 1388.8

Example 16 Abut-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Abut-OH instead of Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (20% after 80% B in 10 min, retention time 4.35 min) was purified.

FAB-MS (M + H) + = 1374.8

Example 17 Gly-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Gly-OH instead of Fmoc-βAla-OH, a crude peptide was obtained as described in Example 1, which was purified using the described chromatography conditions (20% after 80% B in 10 min, retention time 4.45 min) has been.

 FAB-MS (M + H) + = 1346.8

Example 18 βAla-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

Using those described in Example 1

 A crude peptide was obtained for Fmoc-amino acids, which was purified using the described chromatography conditions (20% after 80% B in 10 min, retention time 3.25 min).

FAB-MS (M + H) + = 1213.8

Example 19 Aca-Arg-Phe-D-Ala-Gly-Arg-I le-Asp-Arg-I le-Gly

 Using Fmoc-Aca-OH instead of Fmoc-βAla-OH, a crude peptide was obtained as described in Example 1, which was purified using the described chromatography conditions (20% after 80% B in 10 min, retention time 3.45 min) has been.

 FAB-MS (M + H) + = 1255.8

Example 20 Aund-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-A and OH instead of Fmoc-βAla-OH, a crude peptide was obtained as described in Example 1

 get that using the described

 Chromatography conditions (20% after 80% B in 10 min, retention time 5.15 min) was purified.

FAB-MS (M + H) + = 1325.8

Example 21 Aca-Phe-Arg-Phe-Aoc-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Aoc-OH was as described in Example 1

 Obtain crude peptide using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 7.10 min).

 FAB-MS (M + H) + = 1416.2

Example 22 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Aib-Asp-Arg-Ile-Gly

With the additional use of Fmoc-Aib-OH, a crude peptide was obtained as described in Example 1, which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 5.70 min).

FAB-MS (M + H) + = 1217.8

Example 23 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Aib-Arg-Ile-Gly

Using Fmoc-Aib-OH instead of Fmoc-Asp (tBu) -OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (35% after 65% B in 13.5 min, retention time 3.70 min) was cleaned.

 FAB-MS (M + H) + = 1330.9

Example 24 βAla-Phe-Arg-Phe-L-Btm-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-L-Btm-OH instead of Fmoc-D-Ala-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 5.90 min) was purified.

FAB-MS (M + H) + = 1372.7

Example 25 βAla-Phe-Arg-Phe-D-Btm-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-D-Btm-OH instead of Fmoc-D-Ala-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.05 min) was purified.

 FAB-MS (M + H) + = 1372.7

Example 26 βAla-Phe-Arg-Phe-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-Pro-OH instead of Fmoc-D-Ala-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.15 min ) was cleaned.

FAB-MS (M + H) + = 1386.8

Example 27 βAla-Phe-Arg-Phe-D-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-D-Pro-OH instead of Fmoc-D-Ala-OH was a crude peptide as described in Example 1

 get that using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.35 min) was purified.

 FAB-MS (M + H) + = 1386.8

Example 28

Tyr-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

With the additional use of Fmoc-Tyr (tBu) -OH and without Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 5.40 min).

FAB-MS (M + H) + = 1306.0

Example 29 Tyr (Bzl) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

With the additional use of Fmoc-Tyr (Bzl) -OH and without Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 6.10 min).

 FAB-MS (M + H) + = 1395.9

Example 30 Phe-Arg-Tyr-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

 With the additional use of Fmoc-Tyr (tBu) -OH and without Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 6.55 min).

FAB-MS (M + H) + = 1305.9

Example 31 Phe-Arg-Tyr (Bzl) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

With the additional use of Fmoc-Tyr (Bzl) -OH and without Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 7.10 min).

 FAB-MS (M + H) + = 1395.9

Example 32 βAla-Phe-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-Gly

 Using Fmoc-L-Clg-OH instead of Fmoc-D-Ala-OH was a crude peptide as described in Example 1

 get that using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.90 min) was purified.

FAB-MS (M + H) + = 1400.8

Example 33 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Nle-Asp-Arg-I le-Gly

Using additional Fmoc-Nle-OH, a crude peptide was obtained as described in Example 1, which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.40 min).

FAB-MS (M + H) + = 1360.4

Example 34 βAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile

The peptide synthesis was carried out with an ACT200 peptide synthesizer from Advanced ChemTech using the Fmoc strategy using a modified control program. The 50 ml shaking reactor was charged with 1 g of 2-methoxybenzyl ester resin from Bachem, Switzerland, which was loaded with 0.5 mmol of Fmoc-isoleucine. The following amino acid derivatives were used:

 Fmoc-Arg (Mtr) -OH, Fmoc-Asp (tBu) -OH, Fmoc-Met-OH,

 Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc-Cha-OH, Fmoc-Phe-OH and Fmoc-ßAla-OH. The clutches were under

 Use of 3 equivalents of Fmoc-amino acid, 1-hydroxybenzotriazole and dicyclohexylcarbodiimide (coupling time 40 minutes). To

 The TNBS test was carried out at

 incomplete acylation under the coupling

 Repeated use of the same reagents and excesses. When the acylation was complete, the next synthesis cycle was started. The Fmoc protecting groups were each cleaved with 20% piperidine in DMF (once 3 minutes, once 15 minutes). Between the reactions, the resin was washed 10 times with DMF. After construction of the linear sequence H-ßAla-Phe-Arg (Mtr) -Cha-D-Ala-Gly-Arg (Mtr) -Met-Asp (tBu) - Arg (Mtr) -Ile- on the polymeric support, the resin became

 washed thoroughly with dichloromethane and then 5 times with 20 ml of a 1% solution of

Trifluoroacetic acid in dichloromethane for a maximum of 10 minutes treated at room temperature (until the resin turns intense purple). The solutions were combined and concentrated in vacuo. The residue is triturated with ether, the ether decanted off, the peptide im

 Nitrogen stream dried and in 130ml DMF

 added, the pH adjusted to about 8.5 with triethylamine, the solution cooled to -20 ° C and 0.2g (0.75 mmol) diphenylphosphoryl azide added. It was 48 hours at -20 ° C, 48 hours at 4 ° C

 ditched. The pH was kept at 8.5 with triethylamine. Then DMF was removed in vacuo, the residue was triturated twice with ether, the ether was decanted off and the residue was removed with a

 Nitrogen stream dried. The

 Side chain protection groups were with

 Trifluoroacetic acid / anisole (90/10) 24 hours at

 Split off room temperature. The solution was concentrated in vacuo, the residue was digested with ether and dried. The crude peptide was over a Dynamax C18, 3 u column (10 x 2.14 cm) using a

 Gradients from A: water / acetonitrile /

 Trifluoroacetic acid 95/5 / 0.2 and B: same as 20/80 / 0.2 from 5% B to 80% B in 11 minutes, flow 20 ml, retention time 7.80 minutes, cleaned. After freeze-drying, an amorphous colorless powder was obtained.

 FAB-MS (M + H) + = 1327.9

Example 35 βAla-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (20% after 80% B in 10 min, retention time 3.25 min). FAB-MS (M + H) + = 1156.7

Example 36

Aca-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Ile

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 using the method described

 Chromatography conditions (20% after 80% B in 10 min, retention time 3.70 min) was cleaned.

 FAB-MS (M + H) + = 1198.8

Example 37 Aund-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-A and -OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, using the described

 Chromatography conditions (20% after 80% B in 10 min, retention time 5.55 min) was cleaned.

FAB-MS (M + H) + = 1268.9 Example 38

 Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 using the method described

 Chromatography conditions (20% after 80% B in 10 min, retention time 4.90 min) was cleaned.

 FAB-MS (M + H) + = 1346.2

Example 39 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (20% after 80% B in 10 min, Retention time 4.50 min) was cleaned. FAB-MS (M + H) + = 1304.0

Example 40 βAla-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Asρ-Arg-Ile

With the additional use of Fmoc-Lys (BOC) -OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 using the method described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.10 min) was purified.

 FAB-MS (M + H) + = 1275.0

Example 41 βAla-Phe-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

With the additional use of Fmoc-Lys (BOC) -OH and Fmoc-Ser (Bzl) -OH instead of Fmoc-Cha-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 10 min, retention time 6.20 min). FAB-MS (M + H) + = 1305.0

Example 42 Aca-Phe-Lys-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and Fmoc-Lys (BOC) -OH without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 that using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 6.60 min). FAB-MS (M + H) + = 1318.2

Example 43 Aca-Phe-Lys-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-Ile

 With the additional use of Fmoc-Lys (BOC) -OH and of Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, the procedure was as described in Example 1 obtained a crude peptide which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.40 min).

FAB-MS (M + H) + = 1290.2

Example 44 Aca-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 7.35 min).

 FAB-MS (M + H) + = 1352.2

Example 45 Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and Fmoc-D-Phe-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 , which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.35 min). FAB-MS (M + H) + = 1346.2

Example 46

Aca-Cha-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 7.35 min).

 FAB-MS (M + H) + = 1352.0

Example 47 βAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 5.90 min) was purified.

FAB-MS (M + H) + = 1309.5

Example 48 βAla- (4-NO2) Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 With the additional use of Fmoc- (4-NO2) Phe-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 10 min, retention time 6.85 min) was purified.

 FAB-MS (M + H) + = 1348.9

Example 49 βAla-Phe-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 With the additional use of Fmoc-Lys (BOC) -OH and Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1

 Using the described chromatography conditions (5% after 80% B in 10 min, retention time 6.75 min).

FAB-MS (M + H) + = 1281.9

Example 50 Clg-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Clg-OH instead of Fmoc-ßAla-OH and Fmoclle-OH instead of Fmoc-Met-OH and without Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1 using the method described

 Chromatography conditions (5% after 80% B in 11 min, retention time 7.35 min) was purified.

 FAB-MS (M + H) + = 1259.8

Example 51 βAla- (4-NO2) Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc- (4-NO2) Phe-OH instead

 Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 10 min, retention time 6.50 min) was cleaned.

 FAB-MS (M + H) + = 1354.7

Example 52 βAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-I le-Asp-Arg-I le

 Using Fmoc-Tyr (Bzl) -OH instead of Fmoc-Phe-OH and Fmoc-I le-OH instead of Fmoc-Met-OH was as in

Example 1 described a crude peptide obtained that was purified using the described chromatography conditions (5% after 80% B in 10 min, retention time 8.20 min).

 FAB-MS (M + H) + = 1415.9

Example 53 βAla-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Tyr (tBu) -OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1

 Using the described chromatography conditions (5% after 80% B in 10 min, retention time 6.45 min).

 FAB-MS (M + H) + = 1325.8

Example 54

Thc-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Thc-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1 using the method described

 Chromatography conditions (5% after 80% B in 10 min, retention time 6.45 min) was purified.

FAB-MS (M + H) + = 1279.7 Example 55 βAla-Phe-Ctr-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 With additional use of Fmoc-Ctr-OH and

 Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1, the under

 Using the described chromatography conditions (5% after 80% B in 10 min, retention time 7.00 min) was cleaned.

 FAB-MS (M + H) + = 1310.6

Example 56 Thc-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-The-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1

 Use of the described

 Chromatography conditions (5% after 80% B in 10 min, retention time 7.60 min) was cleaned.

 FAB-MS (M + H) + = 1426.7

Example 57

Clg-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Clg-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1 obtained, which was purified using the described chromatography conditions (5% after 80% B in 10 min, retention time 8.90 min).

 FAB-MS (M + H) + = 1406.7

Example 58 Aca-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

With the additional use of Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a was as described in Example 1 Obtain crude peptide that under

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 5.45 min).

 FAB-MS (M + H) + = 1170.6

Example 59 Aca-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH, Fmoc-Nle-OH instead of Fmoc-Met-OH and Fmoc-Ser (Bzl) -OH instead of Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 , which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 5.70 min). FAB-MS (M + H) + = 1200.5 Example 60 Aca-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

 Under additional. Use of Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-Asp (tBu) -OH a crude peptide was obtained as described in Example 1, using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 7.10 min) was purified.

 FAB-MS (M + H) + = 1089.5

Example 61 βAla-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

 Using Fmoc-Lys (BOC) -OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and

Fmoc-Asρ (tBu) -OH, a crude peptide was obtained as described in Example 1, which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.90 min). FAB-MS (M + H) + = 1160.6

Example 62 Aca-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

Using Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH as in Example 1

 described a crude peptide obtained under

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 5.95 min) was cleaned.

 FAB-MS (M + H) + = 1055.7

Example 63 βAla-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile

 Using Fmoc-Lys (BOC) -OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and

Fmoc-Asp (tBu) -OH, a crude peptide was obtained as described in Example 1, which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 5.90 min). FAB-MS (M + H) + = 1013.6

Example 64 βAla-Phe-Gly-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Using Fmoc-Lys (BOC) -OH and

 Fmoc-Ser (Bzl) -OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80 % B in 11 min, retention time 6.85 min). FAB-MS (M + H) + = 1206.4

Example 65

Aca-Phe-Gly-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and Fmoc-Lys (BOC) -OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 obtained, which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 7.40 min). FAB-MS (M + H) + = 1248.5

Example 66 βAla-Gly-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Using Fmoc-Lys (BOC) -OH and

Fmoc-Ser (Bzl) -OH instead of Fmoc-Phe-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography Conditions (5% after 80% B in 11 min, retention time 5.80 min) was cleaned.

 FAB-MS (M + H) + = 1059.4

Example 67 Aca-Gly-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH, Fmoc-Ser (Bzl) -OH instead of Fmoc-Cha and Fmoc-Nle-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1, which using the

 described chromatography conditions (5% after 80% B in 11 min, retention time 6.20 min). FAB-MS (M + H) + = 1101.5

Example 68 βAla-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Using Fmoc-Ser (Bzl) -OH instead of Fmoc-Cha-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and additionally

Fmoc-Lys (BOC) -OH was obtained as described in Example 1, a crude peptide which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.05 min), FAB-MS ( M + H) + = 1002.6 Example 69 Aca-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-I le

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH, Fmoc-Ile-OH instead of Fmoc-Met-OH and Fmoc-Ser (Bzl) -OH instead of Fmoc-Cha-OH and Fmoc-Lys (BOC) -OH a crude peptide was obtained as described in Example 1, using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.60 min) was cleaned.

 FAB-MS (M + H) + = 1044.5

Example 70

Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Btu-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 using the method described

 Chromatography conditions (5% after 80% B in 11 min, retention time 5.35 min) was purified.

 FAB-MS (M + H) + = 1225.6

Example 71 D-Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-D-Btu-OH instead of Fmoc-ßAla-OH and Fmoc-I le-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 get that using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 5.15 min) was purified.

 FAB-MS (M + H) + = 1225.6

Example 72 βAla-Arg-Phe-D-Ala-Gly-Arg-Ile-Arg-Ile

 Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-Asp (tBu) -OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.15 min) was purified.

 FAB-MS (M + H) + = 1041.5

Example 73

Aca-Arg-Phe-D-Ala-Gly-Arg-Ile-Arg-Ile

Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-Asp (tBu) -OH, a crude peptide was obtained as described in Example 1 obtained, which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.10 min). FAB-MS (M + H) + = 1083.9 Example 74 Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Gly-Arg-Ile

 Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH, Fmoc-Ile-OH instead of Fmoc-Met-OH and Fmoc-Gly-OH instead of Fmoc-Asp (tBu) -OH and without Fmoc-Cha-OH was like in Example 1 obtained a crude peptide obtained using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 5.80 min) was purified.

 FAB-MS (M + H) + = 1331.2

Example 75 Aca-Phe-Arg-Tyr (OMe) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Tyr (OMe) -OH and Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH was as in Example 1

 described a crude peptide obtained under

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.85 min).

 FAB-MS (M + H) + = 1376.2

Example 76 Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-D-Ile-Asp-Arg-Ile

Using Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-D-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1 get that using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 7.10 min) was purified.

 FAB-MS (M + H) + = 1346.0

Example 77

Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-D-Asp-Arg-Ile

Using Fmoc-D-Asp (tBu) -OH instead

 Fmoc-Asp (tBu) -OH, Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.60 min) was cleaned.

 FAB-MS (M + H) + = 1346.0

Example 78

Aca-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-D-Arg (Mtr) -OH and Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH as in Example 1

 described a crude peptide obtained under

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.65 min) was cleaned.

FAB-MS (M + H) + = 1346.0 Example 79 Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-D-Phe-OH and Fmoc-Aca-OH instead of Fmoc-ßAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH was as in Example 1

 described a crude peptide obtained under

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.55 min).

 FAB-MS (M + H) + = 1346.0

Example 80 Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-Aca-OH was as in

 Example 1 described a crude peptide obtained which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.55 min).

 FAB-MS (M + H) + = 1232.5

Example 81 βAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

Using Fmoc-D-Arg (Mtr) -OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.15 min).

 FAB-MS (M + H) + = 1303.7

Example 82 βAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

Using Fmoc-D-Arg (Mtr) -OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.05 min).

 FAB-MS (M + H) + = 1346.0

Example 83 Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 5.45 min).

FAB-MS (M + H) + = 1085.5 Example 84 βAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-D-Arg (Mtr) -OH instead

 Fmoc-Arg (Mtr) -OH and of Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH became as in Example 1

 described a crude peptide obtained under

 Using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.40 min).

 FAB-MS (M + H) + = 1303.7

Example 85 βAla-Phe-Arg-Cha-Azt-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Azt-OH instead of Fmoc-D-Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH was as in

 Example 1 described a crude peptide obtained which was purified using the described chromatography conditions (5% after 80% B in 10 min, retention time 7.20 min).

 FAB-MS (M + H) + = 1321.7

Example 86 βAla-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was obtained as described in Example 1, which using the described Chromatography conditions (5% after 80% B in 10 min, retention time 6.35 min) was purified.

 FAB-MS (M + H) + = 1162.5

Example 87 pArg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 10 min, Retention time 6.10 min) was cleaned. FAB-MS (M + H) + = 1091.5

Example 88 pPhe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-ßAla-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 10 min, Retention time 8.25 min) was cleaned. FAB-MS (M + H) + = 1238.8 Example 89 H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 The peptide synthesis was carried out with an ACT200 peptide synthesizer from Advanced ChemTech using the Fmoc strategy using a modified one

Tax chart. The 50 ml shaking reactor was charged with 1 g of 2-methoxybenzyl ester resin from Bachem, Switzerland, which was loaded with 0.5 mmol of Fmoc isoleucine.

The following amino acid derivatives were used:

Fmoc-Arg (Mtr) -OH, Fmoc-Asρ (tBu) -OH, Fmoc-Nle-OH,

Fmoc-Lys (BOC) -OH, Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc-Phe-OH and BOC-Lys (Fmoc) -OH. The clutches were under

Use of 3 equivalents of Fmoc-amino acid, 1-hydroxybenzotriazole and dicyclohexylcarbodiimide

carried out (coupling time 40 minutes). To

Performing the TNBS test, the coupling was repeated using incomplete acylation using the same reagents and excesses. When the acylation was complete, the next synthesis cycle was started. The removal of the Fmoc protective groups was in each case with 20% piperidine in DMF (once for 3 minutes, once

15 minutes).

Between the reactions, the resin was washed 10 times with DMF. After building up the linear sequence BOC-Lys-Arg (Mtr) -Phe-D-Ala-Gly-Lys (BOC) - Nle-Asρ (tBu) -Arg (Mtr) -Ile- on the polymeric support, the resin was thoroughly washed with dichloromethane washed and then 5 times with a maximum of 20 ml of a 1% solution of trifluoroacetic acid in dichloromethane

Treated for 10 minutes at room temperature (until the resin turns intense purple). The solutions were combined and concentrated in vacuo. The residue is triturated with ether, the ether is decanted off, the peptide is dried in a stream of nitrogen and taken up in 130 ml of DMF, the pH is adjusted to approximately 8.5 with triethylamine, the solution is cooled to -20 ° C. and 0.2 g (0.2 75 mmol) Diphenylphosphorylazid added. It was 48 hours at -20 ° C, 48 hours at 4 ° C

ditched. The pH was kept at 8.5 with triethylamine. Then DMF was removed in vacuo, the residue was triturated twice with ether, the ether was decanted off and the residue was removed with a

Nitrogen stream dried. The

Side chain protection groups were with

Trifluoroacetic acid / anisole (90/10) 24 hours at

Split off room temperature. The solution was concentrated in vacuo, the residue was digested with ether and dried. The crude peptide was passed over a Dynamax C18, 3μ column (10 x 2.14 cm) using a

Gradients from A: water / acetonitrile /

Trifluoroacetic acid 95/5 / 0.2 and B: same as 20/80 / 0.2 from 5% B to 80% B in 11 minutes, flow 20ml,

Retention time 5.25 minutes cleaned. To

Freeze drying gave an amorphous colorless powder.

FAB-MS (M + H) + = 1186.0 Example 90 Z-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH was obtained as described in Example 1, a crude peptide which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.60 min). FAB-MS (M + H) + = 1320.0

Example 91

Z-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and Fmoc-Ser (Bzl) -OH instead of Fmoc-Phe-OH was obtained as described in Example 1, a crude peptide using the described

Chromatography conditions (5% after 80% B in 11 min, retention time 6.95 min) was purified.

FAB-MS (M + H) + = 1350.0

Example 92 Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Using Bz-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH was obtained as described in Example 1, a crude peptide, which using the described chromatography conditions (5% after 80 ° B in 11 min, retention time 6.00 min), FAB-MS (M + H) + = 1290.0

Example 93

Z-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and without Fmoc-Nle-OH and

Fmoc-Lys (BOC) -OH was obtained as described in Example 1, a crude peptide which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.65 min). FAB-MS (M + H) + = 1348.0

Example 94

H-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Cha-OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH, a crude peptide was obtained as described in Example 1 described

Chromatography conditions (5% after 80% B in 11 min, retention time 6.00 min) was purified.

FAB-MS (M + H) + = 1219.7 Example 95

Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH became a crude peptide as described in Example 1 get that using the described

Chromatography conditions (5% after 80% B in 11 min, retention time 6.35 min) was purified.

FAB-MS (M + H) + = 1353.7

Example 96 Menoc-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Menoc-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH became as in Example 1

 described a crude peptide obtained under

Use of the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 8.20 min) was purified.

FAB-MS (M + H) + = 1395.8 Example 97

Menoc-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Menoc-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH Fmoc-Cha-OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH, a crude peptide was obtained as described in Example 1 that using the described

Chromatography conditions (20% after 80% B in 11 min, retention time 7.00 min) was cleaned.

FAB-MS (M + H) + = 1402.0

Example 98

H-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Fmoc-Ile-OH instead of Fmoc-Nle-OH and Fmoc-Cha-OH instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1

Use of the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.40 min) was purified.

FAB-MS (M + H) + = 1191.8

Example 99

Z-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and and Fmoc-Ile-OH instead of Fmoc-Nle-OH, a crude peptide was obtained as described in Example 1, using the described

Chromatography conditions (5% after 80% B in 11 min, retention time 7.75 min) was purified.

FAB-MS (M + H) + = 1326.0

Example 100

Z-Lys-Phe-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH, a crude peptide was obtained as described in Example 1, which using the described chromatography conditions (5% after 80% B in 11 min, retention time 8.40 min) was cleaned.

FAB-MS (M + H) + = 1339.0

Example 101

(4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Using (4-NO ₂ ) Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH, Fmoc-Ile-OH instead of Fmoc-Nle-OH and Fmoc-Cha-OH instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1

Using the described chromatography conditions (5% after 80% B in 11 min, retention time 8.45 min).

FAB-MS (M + H) + = 1398.9

Example 102

Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and additionally

Fmoc-Orn (BOC) -OH was obtained as described in Example 1, a crude peptide which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 7.80 min). FAB-MS (M + H) + = 1311.8 Example 103

H-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Using Fmoc-Ser (Bzl) -OH instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1, which using the described

Chromatography conditions (5% after 80% B in 11 min, retention time 5.55 min) was purified.

FAB-MS (M + H) + = 1216.0

Example 104 Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Using Bz-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH was obtained as described in Example 1, a crude peptide which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 6.40 min). FAB-MS (M + H) + = 1290.0

Example 105

Bz-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

 Using Bz-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and Fmoc-Ser (Bzl) -OH instead of Fmoc-Phe-OH was obtained as described in Example 1, a crude peptide using the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.35 min) was purified.

FAB-MS (M + H) + = 1319.7 Example 106 Bz-D-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

Using Bz-D-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and Fmoc-Ser (Bzl) -OH instead of Fmoc-Phe-OH was obtained as described in Example 1, a crude peptide using the described

Chromatography conditions (5% after 80% B in 11 min, retention time 6.70 min) was purified.

FAB-MS (M + H) + = 1319.8

Example 107

Tos-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Tos-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH, a crude peptide was obtained as described in Example 1, using the described

Chromatography conditions (5% after 80% B in 11 min, retention time 6.90 min) was purified.

FAB-MS (M + H) + = 1367.7

Example 108

H-Lys-Arg-Phe-Clg-Arg-Ile-Asp-Arg-Ile

Using Fmoc-Clg-OH instead of Fmoc-Gly-OH and instead of Fmoc-D-Ala-OH and Fmoc-Ile-OH instead Fmoc-Nle-OH a crude peptide was obtained as described in Example 1, which using the

described chromatography conditions (5% after 80 ° B in 11 min, retention time 4.85 min). FAB-MS (M + H) + = 1253.8

Example 109

Z-Lys-Arg-Phe-Clg-Arg-Ile-Asp-Arg-Ile

Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH, from Fmoc-Clg-OH instead of Fmoc-Gly-OH and Fmoc-D-Ala-OH and from Fmoc-Ile-OH instead of Fmoc-Nle-OH and Without Fmoc-Lys (BOC) -OH became as in Example 1

described a crude peptide obtained under

Use of the described

 Chromatography conditions (5% after 80% B in 11 min, retention time 6.85 min) was purified.

FAB-MS (M + H) + = 1387.8

Example 110

Z-Lys-Arg-Cha-Clg-Arg-Ile-Asp-Arg-Ile

 Using Z-Lys (Fmoe) -OH instead

BOC-Lys (Fmoc) -OH, Fmoe-Cha-OH instead of Fmoc-Phe-OH and Fmoc-I le-OH instead of Fmoc-Nle-OH and Fmoc-Clg-OH instead of Fmoc-Gly-OH and instead of Fmoc-D -Ala-OH and without

Fmoc-Lys (BOC) -OH was obtained as described in Example 1, a crude peptide which was purified using the described chromatography conditions (5% after 80% B in 11 min, retention time 8, 70 min). FAB-MS (M + H) + = 1394 .0 Example 111 Z-Lys-Arg-Cha-D-Clg-Arg-Ile-Asp-Arg-Ile

Using Z-Lys (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH instead of Fmoc-Phe-OH, Fmoc-Clg-OH instead of Fmoc-Gly-OH and Fmoc-D-Ala-OH and Fmoc-Ile-OH instead of Fmoc-Nle -OH and without Fmoc-Lys (BOC) - OH, a crude peptide was obtained as described in Example 1, using the described

Chromatography conditions (5% after 80% B in 10 min, retention time 9.80 min) was purified.

FAB-MS (M + H) + = 1393.9

Example 112

H-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using BOC-Dap (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH became as in Example 1

described a crude peptide obtained under

Use of the described

 Chromatography conditions (5% after 80% B in 10 min, retention time 6.85 min) was purified.

FAB-MS (M + H) + = 1177.5 Example 113

Z-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Using Z-Dap (Fmoc) -OH instead

BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and Without Fmoc-Lys (BOC) -OH became a crude peptide as described in Example 1 get that using the described

Chromatography conditions (5% after 80% B in 10 min, retention time 8.10 min) was purified.

FAB-MS (M + H) + = 1311.6

The following were produced analogously:

(4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile

 Cleaning using the described

Chromatography conditions (10% after 90% B in 10 min, retention time 7.4 min) FAB-MS (M + H) + = 1417.0

(4-NO ₂ ) Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 Cleaning using the described

Chromatography conditions (10% after 90% B in 10 min, retention time 7.8 min) FAB-MS (M + H) + = 1356.6 Example 114

2-pyridylacetyl-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

 The peptide synthesis was carried out with an ACT200 peptide synthesizer from Advanced ChemTech using the Fmoc strategy using a modified one

Control program. The 50 ml shaking reactor was charged with 1 g of 2-methoxybenzyl ester resin from Bachem, Switzerland, which was loaded with 0.5 mmol of Fmoc isoleucine. The following amino acid derivatives were used:

Fmoc-Arg (Mtr) -OH, Fmoc-Asp (tBu) -OH, Fmoc-Ile-OH,

Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc-Cha-OH and

2-pyridylacetyl-Lys (Fmoc) -OH. The couplings were made using 3 equivalents each

Fmoc amino acid, 1-hydroxybenzotriazole and

Dicyclohexylcarbodiimid performed (coupling time 40 minutes). After the TNBS test had been carried out, the coupling was removed with incomplete acylation

Repeated use of the same reagents and excesses. When the acylation was complete, the next synthesis cycle was started. The Fmoc protecting groups were each cleaved with 20% piperidine in DMF (once 3 minutes, once 15 minutes).

Between the reactions, the resin was washed 10 times with DMF. After building up the linear sequence 2-pyridylacetyl-Lys-Arg (Mtr) -Cha-D-Ala-Gly-Arg (Mtr) - Ile-Asp (tBu) -Arg (Mtr) -Ile- on the polymeric support, the resin became thorough washed with dichloromethane and then 5 times with a maximum of 20 ml of a 1% solution of trifluoroacetic acid in dichloromethane

Treated for 10 minutes at room temperature (until the resin turns intense purple). The solutions were combined and concentrated in vacuo. The residue is triturated with ether, the ether is decanted off, the peptide is dried in a stream of nitrogen and taken up in 130 ml of DMF, the pH is adjusted to approximately 8.5 with triethylamine, the solution is cooled to -20 ° C. and 0.2 g ( 75 mmol) Diphenylphosphorylazid added. It was 48 hours at -20 ° C, 48 hours at 4 ° C

ditched. The pH was kept at 8.5 with triethylamine. Then DMF was removed in vacuo, the residue was triturated twice with ether, the ether was decanted off and the residue was removed with a

Nitrogen stream dried. The

Side chain protection groups were with

Trifluoroacetic acid / anisole (90/10) 24 hours at

Split off room temperature. The solution was concentrated in vacuo, the residue was digested with ether and dried. The crude peptide was passed over a Dynamax C18, 3μ column (10 x 2.14 cm) using a

Gradients from A: water / acetonitrile /

Trifluoroacetic acid 95/5 / 0.2 and B: same as 20/80 / 0.2 from 10% B to 90% B in 11 minutes, flow 10ml / min,

 Retention time 8.2 minutes cleaned. To

 Freeze drying gave an amorphous colorless powder.

FAB-MS (M + H) + = 1338.6 Examples 115 to 124 X-Lys-Arg-Cha-D-Ala-Gly-Arg-I le-Asp-Arg-Ile

 Using X-Lys (Fmoc) -OH instead

 2-Pyridylacetyl-Lys (Fmoc) -OH was a crude peptide obtained as described in Example 1, which under

 Using the described chromatography conditions (10% to 90% B in 11 min, retention time see table below).

(1): Deviation from cleaning according to Example 1: 10% B to 90% B in 10 minutes, flow 10 ml / min.

Gel (for transdermal administration, especially

associated with iontophoresis)

10% active substance of the general formula I in

 Citrate buffer pH 4.1

 (Composition see below)

0.25% agarose

Composition citrate buffer pH 4.1

10.5 g citric acid monohydrate

100.0 ml of sodium hydroxide solution 1 mol / l solution I ad 500.0 ml of distilled water

100.0 ml hydrochloric acid 0.1 mol / l

ad 250.0 ml solution I solution II

 The above solution is heated to about 60 ° C. with stirring and after dissolution of all agarose particles

Let the room temperature cool down.

Solution for injection:

10.5 g NaH ₂ PO ₄ . 2H ₂ O

95.5 g Na ₂ HPO ₄ . 12H ₂ O buffer

 22.0 g NaCl pH 7.4

to 5,000 ml of distilled water

This buffer solution is autoclaved for 30 minutes at 121 ° C and 1 atm. 1.5 g of active substance of the general formula I are weighed into this solution and the entire solution is sterile filtered.

In these preparation examples, e.g. the

connection

(4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

or one of the other compounds mentioned above can be used.

Claims

Claims 1. Cyclopeptides of the general formula I with ANP  agonistic effect, An-Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn (I)

 where the sequence of links Bn to Kn is the sequence of amino acid residues of hANP  Arg (27) -Phe (8) -Gly (9) -Gly (10) -Arg (11) - Met (12) -Asp (13) -Arg (14) -Ile (15) - or their  spatial structural and functional equivalents and An is a spacer group that Bn with Kn  connects and the spatial structure of each  Molecule influenced in that the  Bind cyclopeptides to ANP receptors and their pharmaceutically acceptable salts. 2. Cyclopeptides according to claim 1, wherein the spacer group An contains an aromatic or cycloaliphatic radical in the part closest to the Bn member. 3. Cyclopeptides according to claim 1 or 2, wherein the Links Bn, Cn, En, Fn, Gn, Hn, In and Kn are in the L-form. 4. Cyclopeptide according to any one of claims 1 to 3, wherein Bn is an α-amino acid residue with one or two  Is side chains, wherein the side chain (s) or one of the two side chains contains one, two, three or four basic group (s); Cn is an α-amino acid residue with one or two  if desired, -O-, -O- or -C (O) O- containing alkyl side chains, the side chain (s) or one of the two  Side chains carries one or two residues, the respective residue being cycloalkyl having 3 to 10 carbon atoms, phenyl,  Naphthyl, substituted (e.g. hydroxy, Is phenyl (C ₁ -C ₄ ) alkyloxy, (C ₁ -C ₄ ) alkoxy, NO ₂ ) phenyl or a 5- or 6-membered aromatic heterocycle, in which 2 members are N or one member N and one member O or S. is or a member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,  Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl; Dn and En  are independently Gly or an α-amino acid residue that mimics the spatial structure of the native amino acid Gly, or Dn and En  together an ω-amino acid residue -NH- (CH ₂ ) _{2-1 1} -CO- or a peptide template; Fn is an α-amino acid residue with one or two  Is side chains, wherein the side chain (s) or one of the two side chains contains one, two, three or four basic group (s); Gn an α-amino acid residue with one or two  is lipophilic side chains; Hn is Gly or an α-amino acid residue which has no functional group in the side chain (s) or -COOH or -CONH ₂ as functional  Group contains; In an α-amino acid residue with one or two  Is side chains, wherein the side chain (s) or one of the two side chains contains one, two, three or four basic group (s); Kn an α-amino acid residue with one or two is lipophilic side chains. 5. Cyclopeptide according to claim 4, wherein Bn, Fn and In independently represent an α-amino acid residue with a side chain, in which the side chain contains one or two basic group (s); Cn is an α-amino acid residue with a side chain; Dn and En are independent as defined in claim 4 or  Dn and En together have an ω-amino acid residue -NH- (CH ₂ ) _2-5 -CO- or a peptide template  mean; Gn and Kn independently of one another  α-amino acid residue with a lipophilic  Side chain mean, the side chain Is (C ₁ -C ₈ ) alkyl, which may also contain one or two -S- or -O- in the chain; Hn Gly or an α-amino acid residue is its Side chain (C ₁ -C ₆ ) alkyl, Phenyl- (C ₁ -C ₆ ) alkyl, H ₂ N-CO- (CH ₂ ) _1-4 - or HOOC- (CH ₂ ) _1-4 -. 6. The cyclopeptide of claim 5, wherein Bn, Fn and In are independently Arg, D-Arg, Lys, D-Lys, Orn, D-Orn, Homo-Arg, D-Homo-Arg, Dap, D-Dap or 4-Amino-Phe, preferred Arg, D-Arg, Lys, D-Lys or Orn; Cn Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha, Ser (Bzl), D-Ser (Bzl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr (Bzl), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or D-Glu (Bzl), preferably Phe, Cha, Tyr, Nal, Tyr (Bzl) or (4-NO ₂ ) -Phe; Dn and En are independently Ala, Gly, Pro, Ser, Asn, Lys, Asp or Thr or their D-form, preferably Dn D-Ala, Gly, Pro, D-Pro, Ser or D-Ser; En is Gly, Asp or Asn; or Dn and En together are an ω-amino acid residue of the formula -NH- (CH ₂ ) _2-5 -CO- or a peptide template, preferably Btu, Clg, The or Trc or their  D forms, especially D-Btu; Gn and Kn are independently Ile, D-Ile, Met, D-Met, Nle, D-Nle, Leu, D-Leu, Val or D-Val, preferably Ile, Met, Nle or Leu; Hn HOOC- (CH ₂ ) _1-4 -CH (NH -) - CO-, their D-forms,  Is Gly, Ala, D-Ala, Asn, D-Asn, Phe or D-Phe, preferably Asp, Glu or Gly. 7. Cyclopeptide according to one of claims 1 to 6, wherein An a) is the group -A ₁ - A ₂ - A ₃ -, wherein A _{1 is} Gly or an α-amino acid residue, the Side chain (s) does not carry a functional group; A _{2 is} a covalent bond or  ω-amino acid residue of the formula - NH - (CH ₂ ) _n - CO - (II), where n is an integer from 1 to 11; An α-amino acid residue with one or two  if desired, is -O-, -S- or -C (O) O- containing (n) alkyl side chains, the side chain (s) or one of the two side chains carrying one or more residues, the respective residue having cycloalkyl 3 to 10  Carbon atoms, phenyl, naphthyl,  substituted (e.g. hydroxy, Phenyl (C ₁ -C ₄ ) alkyloxy, (C ₁ -C ₄ ) alkoxy, NO ₂ ) is phenyl or a 5- or 6-membered aromatic heterocycle, wherein 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the remaining members are C, preferably Thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl; or b) the group is -A ₄ - A ₅ -, wherein A _{4 is} a peptide template or an ω-amino acid residue  of the formula - NH - (CH ₂ ) _n - CO - (II) where n is an integer from 1 to 11; A _{5 is} a covalent bond or  α-amino acid residue with one or two  if desired -O-, -S- or -C (O) O- containing alkyl side chain (s), the side chain (s) or one of the two  Side chains carries one or two residues, the respective residue being cycloalkyl having 3 to 10 carbon atoms, phenyl,  Naphthyl, substituted (e.g. hydroxy, Phenyl (C ₁ -C ₄ ) alkyloxy, (C ₁ -C ₄ ) alkoxy, NO ₂ ) is phenyl or a 5- or 6-membered aromatic heterocycle, wherein 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the remaining members are C, preferably Thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl; or c) an amino acid residue of the formula III -NH- (CH ₂ ) _m -CH (R) -CO- (III) is where  is an integer from 1 to 11 and R NHX, OX, SX, NXY, -NH (H) -C (O) -CH ₂ -X ¹ , -N (H) -C (O) -CH ₂ -OX ¹ , -N (H) -C (O) -X ¹ , -N (H) -C (O) -CH = CH-X ¹ or -N (H) -C (O) -O-CH ₂ -X ¹ . wherein X represents hydrogen, an unsubstituted or substituted benzoyl radical, one  unsubstituted or substituted cyclohexyloxycarbonyl, an unsubstituted or substituted Benzyloxycarbonylrest, a 2-, 3- or  4-pyridylmethyloxycarbonyl radical or one Tosylrest stands,  Y represents a C1 to C14 alkyl radical or aryl (C1 to C14 alkyl) radical and X ¹ (α) phenyl, (ß) by 1, 2 or 3  Substituent (s): halogen, trifluoromethyl or nitro) substituted phenyl, (γ) naphthyl, (δ) benzo [b] thienyl, (ε) pyridyl or (n) pyrazinyl. 8. Cyclopeptide according to claim 7, wherein An a) is -A ₁ -A ₂ - A ₃ -, wherein A ₁ is  α-amino acid residue with one Is (C ₁ -C ₈ ) alkyl side chain; A _{2 is} an ω-amino acid residue of Formula II. wherein n is an integer from 1 to 6; A _{3 is} an α-amino acid residue with a side chain; or b) the group is -A ₄ - A ₅ -, wherein A _{4 is} a  is ω-amino acid residue of formula II, wherein n is an integer from 1 to 6; A _{5 is} an α-amino acid residue with a side chain; or c) an amino acid residue of the formula III, in which m is 1, 2, 3 or 4 and R is -NHX, -NXY, - -NH (H) -C (O) -CH ₂ -X ¹ , -N (H) -C (O) -CH ₂ -OX ¹ , -N (H) -C (O) -X ¹ , -N (H) -C (O) -CH = CH-X ¹ or -N (H) -C (O) -O-CH ₂ -X ¹ . 9. Cyclopeptide according to claim 8, wherein An a) is the group -A ₁ - A ₂ - A ₃ -, wherein A _{1 is} Ala, Gly, Phe, Val, Ile, Leu or Nle or their D-form, preferably Gly, Ala or D-Ala; A _{2 is} an ω-amino acid residue of formula II, wherein n is 2, 3 or 5; A ₃ Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha, Ser (Bzl), D-Ser (Bzl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr- (Bzl), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D- Asp is (Bzl), His or D-His, preferably Phe, Tyr, Cha, Nal or (4-NO ₂ ) Phe; or b) the group is -A ₄ - A ₅ -, wherein A _{4 is} a ω-amino acid residue of formula II, wherein n is 2, 3 or 5; A ₅ Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha,  Ser (Bzl), D-Ser (Bzl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr (Bzl), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or D-Glu (Bzl), preferably Phe, Tyr, Cha, Nal or (4-NO ₂ ) -Phe; or c) an amino acid residue of formula III, wherein m is 1, 2, 3 or 4 and R is as defined in claim 8, wherein X represents hydrogen, an unsubstituted or chloro, methoxy or (C1 to C3) alkyl substituted benzoyl radical, cyclohexyloxy or menthyloxycarbonyl radical, an unsubstituted or methoxy, nitro, trifluoromethyl or cyano substituted benzyloxycarbonyl radical, preferably benzyloxycarbonyl,  4-methoxybenzyloxycarbonyl, 2- or  4-trifluoromethylbenzylcarbonyl or  4-nitrobenzyloxycarbonyl, especially for  Benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or 2- or 4-trilfuormethylbenzyloxycarbonyl, Y represents a C1 to C14 alkyl radical or (C1 to C14 alkyl) phenyl radical, preferably benzyl or phenylethyl; and X ¹ for phenyl or mono- or  di-substituted phenyl, 2-pyridyl, 2-pyrazinyl, 3-benzo [b] thienyl, or 2-naphthyl. 10) Cyclopeptide according to any one of claims 1 to 9, wherein At the group -A ₁ - A ₂ - A ₃ - is in which A _{1 is} Gly, A ₂ Aca, ßAla, Apen, Abut, Gly or a covalent Bond is, and A _{3 is} Phe, Phe (4-NO ₂ ), Tyr or Tyr (Bzl); or To the group - A ₄ - A ₅ - is where A _{4 is} βAla, Aca, The, Aund, Btu or D-Btu, and A _{5 is} a covalent bond, Phe, D-Phe, Is Phe (4-NO ₂ ), Tyr, Tyr (Bzl) or Cha; or An amino acid residue of formula III -NH- (CH ₂ ) _m -CH (R) -CO-, wherein m is 1 or 4 and R is the group -NHX, where X is H, Z, Bz, Menoc, (4-NO ₂ ) Z or Tos or An X ^{2 is} -Lys-, wherein X ^{2 is} one of the following groups

Bn is Arg, D-Arg, Lys, Orn, or Ctr;  Cn is Cha, Phe, Ser (Bzl), Tyr, Tyr (Bzl) or Tyr (Me); Dn is D-Ala, Pro or D-Pro;  En is Gly;  or  Dn and En together are L-Clg, D-Clg or D-Btu; Fn is Arg or Lys;  Gn is Ile, D-Ile, Nle or Met;  Hn is Asp, D-Asp or Gly;  Is in Arg or D-Arg; and  Kn Ile is. 11. The cyclopeptide of claim 10, wherein At -Gly-ßAla-Phe-,  -Gly-ßAla-Tyr (Bzl) -,  -ßAla-Phe, -ßAla-Phe (4-NO ₂ ) -Lys-, - (4-NO ₂ ) Z-Lys-, is;

 Bn is Arg, Lys, Ctr or Orn;  Cn is Cha or Phe;  Dn D-Ala is.  En is Gly;  Fn is Arg;  Gn is Ile or Met;  Hn Asp;  In Arg is and Kn Ile is. 12. Cyclopeptide according to claim 1, ßAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

ßAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

ßAla-Phe-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

ßAla-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

ßAla-Phe-Ctr-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

(4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

X ² Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

where X is ² ,

(4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile

(4-NO ₂ ) Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

and their pharmaceutically acceptable salts. 13. A process for the preparation of a cyclopeptide according to any one of claims 1 to 12 or its salt, characterized in that according to  Peptide chemistry known linear methods  Sequence of the peptide from the corresponding  Builds up fragments and then these  cyclized and, if desired, into the  appropriate salt transferred. 14. Pharmaceutical preparation containing one  A compound according to any one of claims 1 to 12. 15. Use of a connection according to one of the  Claims 1 to 12 for the manufacture of a  Antihypertensive or hypotensive. 16. Use of a connection according to one of the  Claims 1 to 12 for the manufacture of a  Diuretic. 17. Use a connection according to one of the  Claims 1 to 12 for the manufacture of a  Vasodilators. 18. Use of a connection according to one of the  Claims 1 to 12 for the manufacture of a  Antispasmodic. 19. Use of a connection according to one of the  Claims 1 to 12 for the manufacture of a  Broncholytic.