SK32693A3 - 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

Technical field

The invention relates to novel cells which are made up of unnecessary tissues. natural and unnatural amino acids, their production and use as pharmaceuticals. The peptides are ΛΝΡ-agons with those. .

The novel cyclopep t.i.dy represent partial sequences, partial sequences di terminus not interconnected, i, modified partial sequences and analogs of the so-called atrial to triuretic factors, ANP or at least other triauretic factors. re ti okých pcpt.idov.

BACKGROUND OF THE INVENTION

ANP is synthesized mainly in muscle cells of the heart chambers, there is also deposited as prohormone by those released by mechanical irritation by increased wall tension. It acts as a blood vessel relaxant, lowers blood pressure, acts both uretically and salutically, increases glomerular filtration, reduces plasma volume, increases hematocrile, decreases plasma renin activity and aldostron levels in the plasma, acts. spmasmoly Bowel smooth muscle and bronchiolytics. The action is readily reduced by specific receptors.

L

In this specification and in the claims, the abbreviations used in accordance with the recommendations and IUPAC-IUB.1 of the Commission of Biochcmica l Nomenclaturc (Eur. J. Biochcm. 138,9-37, 1984) are used. Other abbreviations have been used, which are explained below.

AUNDE w -am inoundecan acid i Abu t - - am i nomas 1 verified acid AOC ω-am inoctanoic acid i Apen δ-am inopentanoic acid Aca ß - am i nokap rófium acid acid Aib «-Am i no i zomas 1 y acid Ala and 1 thi n Ala P - or 1 or n Arg and rg i n n Asp aspartic acid i AZT 0 II | N - C | bang to t-butyloxymethyl BOC t. but 1 oxycycarbones 1 B tu 3-amino-1-carboxymethyl-pyrrolidin-2-one B of i. benzy .1. bz benzoy1 ha ey k 1 both x y 1 and 1 is t Cle eyk.l oleuc i n CIG 3-Amino-1- or hydroxymethyl-1-hexahydro-pyrazine Ctr c i t r u 1 i n Dap 2,3-L-diamino-propionic acid DM F N, N - d i me ty 1 forms i d DPPA di-phenyl. phosphorus laz i d DCC d icyk 1ohexylcarbodi im i d DIC d iisopropylcarbodiamine d Gly gl.ye í n His b i s t i d i n HOB t 1 - hydroxybenzo triazole 1 Ile i from l.eue i n Leu 1 euc i n Lys 1 y s i n

-one

Name names 1 oxycarcarones

Me mety I

Met met i on i n

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

Nal · 1 - nať I and Ianí n

No cn ₃ - (α ₂ ) ₂ - ^{α |} (Νΐι ₂ ) -COOII

Or n oi.-n.it.in

Phe phenylalanine

Pmc pentamethylammonium sulfonate l

Ser serín

The 3-amino-7-carboxy-thiophene-1-yn-1-one

Thi * S

CH ₂ -CH (NH ₂ ) -COOH

Tos

Plt

Trt three

Tyr tyrosine

Val. val í n

From benzyloxycarbones1

The term amino acid includes (unless expressly indicated otherwise) natural and unnatural amino acids, as well as their D- and L-forms. The term -amino acid also includes α, α-d is substituted amino acids.

If the amino acid is shown without a pre-mix (e.g., Orn), it is an L-ionic amino acid. The D-form is strongly indicated (D-Orn).

SUMMARY OF THE INVENTION

The invention relates to the cyclopeptides of the general formula I with ANP agonist activity ρΛη-Bn-Cn-Dn-En-ln-Gn-Hn-I n-Kn ..... j (I) wherein the sequence of members Bn to Kn is a sequence of amine acidic new residues of ANP

-Arg (27) -Phe (8) -Gly (9) -G 1 y (Ί G) -Arg (11) -Met (I2) -Asp (13) -Arg (14) lle (15) - or its receptor structure and functional equivalents, An, is a spacer group that associates Bn with Kn and affects the spatial structure of these molecules by binding to the ANP receptors and their pharmaceutically acceptable salts.

Preferred are cyclopeptides in which the spacer group An in the portion downstream of the member Bn contains an aromatic or cycloaliphatic residue.

Most of the amine acid residues may be in the form of I) or L. However, cyclopeptides in which most or all members of Bn, Cn, En, En, Gn, In, In and Kn are in L-form are preferred.

The limit group An maintains α-C-atoms of Bn and Kn members at a distance of 5 to 15 Angstroms. (Conformation and 2D-NMR measurements in aqueous solution, results of limiting conditions to simulate molecular dynamics).

However, An does not bind to the AN? -Buttons, but it affects the ability to bind to receptors and hence the pharmacological activity of the cyclic peptides of the general formula I.

Amino acid residues or peptide templates (as well as I, - forms as well as D-forms) which cause the cyclopeptides of formula I to bind to ANP receptors are considered to be spatially structural and functional equivalents of amino acid residues of ANP. Research carried out so far has shown that eg. The sequence (Bn to Kn) -Arg-Cha-D-Ia-Gly-Arg-1e-Asp-Arg-II shows very good receptor binding values and pharmacological activity. The individual members of the sequence are replaced by releasable residues of similar spatial structure and / or function, whereby the ability to bind to receptors is more or less affected, and in many cases the pharmacological activity varies within the known ag-agonist activity. Variations in individual members can affect the type, size and duration of pharmacological activity. If more than one of the members Bn to Kn is altered, then to the knowledge of the art, the pharmacological efficacy is altered. consists of changes corresponding to unity and exchange variations. In the following list, structurally similar examples of the relationship between receptor binding capability and sequence of members of the cyclopeptides of formula (I) are described below under the heading ANP-Receptor Binding.

Compounds marked with *) have - x bonds in the above assay

IC 50 - here less than 5.10 mol, other compounds have less affinity.

A *) p βα 1a - Phe-Λ g - Phe - Ι) - Λ I aG I y - A-g-II e-Asp-A g g-II e B) pβΛΙa-Phe-Ag-Phe-D-Λ Ia-Gly-Alg-I c-Asp-DA-lg-I e

_Γ C βΛ1a-Phe-D-ll e-Phe-D-Ala-Gly-ΛIa ALG-1 le-Asp-D-ll e-Γ1 eD ') Z - Dap-and R-B C'ha- Λ I and G I γ -A g g-II e-Asp-Λ g-J I e

E11-Dap-Alg-Cha-D-Al I-G Iy-Alg-Ie-Asp-Alg-Ie

G *) p β A I a - Phe - A g g - Phe - D - Λ I a-G I y - A g g-I I e - Asp - A g g-I I e -i

II »)-βΑ I α-Phe-Alg-Phe-D-a I aG IyA g lg-I le-Asp-g ll-Phe - D-Λ lg - Phe - D- Λ I aG I y - A g g-II e-Asp-D-Λ g g-II e)) -β ΛΊ a-Phe-Arg-Cha-B-Ala-Gly-Ag-I e-Asp-A.g -I le-βΑ I α-Aβ-Cha-DA I αG γ-Aβ-Iβ e-Asp-Aβ-I le7

As already mentioned, the term amino acids includes both natural and unnatural amino acids. The non-native amino acids are preferably, if not explicitly, given the narrower meaning given their

molecular hino t wear, eventually: side by side i chain, those of which the size of natural amino acids í n. Akí) salts come into considerations with 1 i with phys : i o 1og i at - j a teľnou i inorganic or organic acids other than na p- IICI , HBr, II ₂ SO ₄ , H ₃ PO ₄ , acid: 1 teaches me new, acidic i fumaric acid 1 i to e.i t tonal, acid on wine, acidic to oe to-

acid.

Centers eh i. the novel peptides may have the R, S or R, S configuration.

The terms Bn, Fn, I n correspond to Arg (27), Arg (11) or A.Ig (14) ΛΝΡ or ih with spatially structural and functional equivalents. The Bn, Fn In, independently of one another may be new amino acids having two basic side chains or, preferably, one basic side chain. A basic side chain is preferably understood to be an alkyl or eyed side chain which contains 1 to 4 (preferably 1 or 2) basic groups. Suitable basic groups are e.g. Example l.tul -NH-, = NII, _-NH2, -IIN -C (NII) _-NH? -C (NII) -ΝΗ ₂ . Preferably, at least one of the side chain basic groups is a double bond. Further preferred are side chains whose first basic group is linked to a δ-carbon atom of the--amino acid or to a carbon atom which is further located in the peptide chain. 6, especially 3 or 4 carbon atoms and cycloalkyl side chains - (CH ₂ ) _y - {C 1 - (Cl 1 ₂ ) -, wherein x and y are independently of each other or 2 and (CA) represents cycloalkyl having 5 or 6 carbon atoms. Preferably, they are basic groups at the end of the side chain.

The

The Cn term corresponds, as already mentioned, to Phe (K) ANP or its structural or functional equivalents. Cn can be an alpha-amine acid residue with two lipols with other side chains or preferably one with another side chain. A lipophilic side chain at this position is considered to be an alkyl side chain of 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, especially 1 carbon atom). These side and I truss chains may contain one or two oxy (-O-), thio (-S-) or -C (O) O- groups. These side alkyl chains carry one or two residues. These radicals are, independently of one another, C 1 to 10 and very light (preferably C 1 to 10) residues, containing 3 to K), preferably 4 to 7 carbon atoms. The aromatic moiety is preferably phenyl, naľtyl, substituted (e.g., N0 _2, hydroxy, fans I (Cj_ ₄₎ and IkyIoxy or (C | _ ₄₎ alkoxy, or attributed to the 5-or 6-membered aromatic optionally also beiízokondenzovaný U.S. heteroeyk 1 comprising 2 N atoms or as one N member and one O or S ring member or contains N, S or O and the other ring members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pirimidinyl, py ridazines I., indolyl, quinolines, quinolines, chromanyl, thiazolyl, oxazolyl, morpholinyl.

The terms Dn and En correspond to Gly (9) or Gly (10) of ANP or its spatially structural or functional equivalent by m.

Dn and En may independently represent Gly or a radical '-amino acid, the structure of the native amino acids together represent ίύ-am inokyseI the new mimic of the EC Torr (Gly), or Dn and En may moiety. -NH (CII _{2) 2} _ , -CO or peptide template. In the positions Dn and En, preferably amine oxides of new residues which, according to statistical analysis

Chou-a Fasman (Biophysical Refl. I, Vol. 2b, 1979, 3b, 7)

-383) are often found in β-condensation i. Preferred are e.g.

Other adherents that occur in an increased number at positions i + 1 and i +2, in particular those with a frequency of 1.06 (Table 1 of the above-mentioned publication).

Suitable peptide templates are understood to be those which otherwise conform to β-ω-wicking.

'í

The members Cn and Kn correspond, as already mentioned, to Met;

(12) where appropriate, clay (15) ΛΝΡ or its spatially structured and functional equivalent. Gn and Kn can each independently be an α-amine acidic residue with two lipols in each side chain, or preferably in one side chain. Lipolians Another side chain in these positions ro- ·!

it is an alkyl side chain having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, in particular a chain having at least three carbon atoms. These alkyl side chains may additionally contain one or two oxy (-O-) or thio (-S-) groups (such as in the meth key). These side chains may also contain 1 to 2 alkyl radicals. .

i (

As mentioned, the term lln corresponds to Asp (13) ΛΝΡ or its spatially structural and functional equivalents.

The member acts as a spacer, and may be an amino acid residue, namely a Gly or a residue that has no functional group in the side chain or -COOH and / or -CONI. Preferably, the side chain is an alkyl group. a side chain of 1 to 6 (preferably 1 to 3) carbon atoms, which may also carry a phenyl group and / or HOOC (C 14) 14 or I 4 N-CO (ΟΙ ₉ ) [4-.

ο

An is, as already mentioned, a metal group. It can even buy it

a) group -Aj-A ₂ -A ₃ - b) group -A ₄ -A ^ - I ') group am i nokyse1 i ny of of formula ! 1 1 -Nll- (012) ,,, -01 (R) - -what- (III). ^A 1 can mean Gly or Rest (t-am i nokynynynyy

two side chains and preferably one side chain. These side chains do not carry any functional groups. Preferably, such a side chain is a branched or unbranched alkyl side chain of 1 to 6 carbon atoms.

A2 is a metal bond only or

A novel radical of formula (II)

-NH- (Cl ₂ ) _n -CO- (II) wherein n represents a number from I to 11 (preferably 1 to 6).

A ₃ can be an α-amino acid residue with two side-chain and, preferably, one side-chain. A common side chain at this position is an alkyl side chain of 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, especially one carbon atom). These alkyl side chains may contain one or two oxy (-O-) or -C (O) O-groups. These alkyl side chains carry one or two residues. These radicals are independently cycloaliphatic or aromatic radicals. The cyclic radical (preferably a cycloalkyl radical) contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic radical is preferably ľeny], naphthyl, substituted (e.g., N0 _9, hydroxy, ľeny I (Cj_ ₄₎ alpha Ikoxy or C | _ ₄ alkoxy) or a 5- or enyl 0členný optionally benzofused aromatic Rocy front of that one of us. wherein the 2 ring members are N or one member is N and one is 0 or S, or one member is N, S or 0 and the other are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl , pyridazinyl I, indolyl, isoquinolyl. , eh i no! y I, eh novels 1, thiazolyl, oxazolyl, mor rol inyl.

A ₄ may be a peptide template or an N-amino acid residue of formula II

-NH- (CII ₂₎ ,, - CO (II) wherein n is an integer from 1 to 11 (preferably to 6);

peptide templates include groups such as Glg, B tu, The and Tre.

or -C (O) () - a day or two residues

A 1 may be a covalent bond with two other side chains of one side or another side chain. Thus, at this position, another side chain is an alkyl side chain having 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, in particular one carbon atom). The alkyl side chain may contain one or more oxy groups (-O-), thio groups (-S-). This alkyl side chain carries them. These radicals are independently cycloaliphatic or aromatic radicals. The cycloaliphatic moiety (preferably a cycloalkyl radical) contains 3 to 10 carbon atoms, preferably 4 to 7 carbon atoms. The aromatic radical is preferably feny1, naphthyl, substituted (e.g., N () _2, hydroxy, ľeny I _(t C ₄₎ - alkoxy, and I, or C ₄ alkoxy, and I) fény.1 or a 5- or 6-membered aromatic optionally benzo-fused heĽeroeykIus wherein the 2 ring members or the amine isocyanate by chains or preferably

Pyrolyl.1, imidazolyl, pyazolazol, pyridyl, pyridyl, pyridazinyl, indidolyl, isoquinolyl, nyl, thiazolyl, oxazolyl, inorololinyl.

An amino acid may also be of formula III -Nll- (CII ₂₎ ', CH (R) -CO- (III) wherein R 11 is a NIIX, ΟΧ, SX, NXY, - NI I (11) - C ( O) - Cl ₁₂ -N (II) -C (O) -CII ₂ -N (1 ') -C (O) -X ¹ , -N (II) -C (O) -C 11 = (-N ( II) -C (O) -O-Cl wherein are N or one member is N and one is O or S, or one member is N, S or O and the others are C, preferably thienyl, luryl, pyrazinyl, pyrimidine, the radical of the radical m is an integer of 1 to

X ¹ and A, ox ¹ ,

111 - X ¹ or l _? -X ¹ ,

X is hydrogen, unsubstituted or substituted benzoyl, unsubstituted or substituted cyclohexylcarbonyl, unsubstituted or substituted benzyloxycarbonyl, 2-, 3- or 4-pyridylmethoxycarbonyl or tosyl,

Y represents a C1-C14-alkyl radical or an aryl- (C1-C14-aalkyl) radical and χΐ is (a) phenyl, (β) 1, 2 or 3 substituents (substituents:

halogen, trifluoromethyl I or nitro substituted phenyl, (γ) naphthyl, (25) benzo / h / thienyl, (f) pyridyl or (4j) pyrazines I.

Preferred is an amino acid residue of formula III when m is 1, 2, 3 or 4 and R-NIIX, -NXY,

-NH (H) -C (O) -CH ₂ -X ¹ ,

-N (II) -C (O) -C 11 ₂ -OX ¹ ,

-N (H) -C (O) -X ¹ ,

-N (II) -C (O) -CII = CH-X ¹ -N (H) -C (O) -O-Cl-X ¹ .

and I or

Preferred are the cycles of the above formula wherein

Bn, En, and In independently of each other are Arg, D-Arg, Lys, l) -Lys, Orn, D-Orn, homo-Arg, D-honio-A rg, hup, D-Dup or 4-amino- Phe, preferably Arg, D-Acg, Lys, D-Lys or Orn,

Cn is Phe, D-Phe, 4-NO ₂ -Phe D-Ser (Bzl), Tyr, D-Tyr, D-Tyr, D-Na'l, Thi, D-Thi, Asp (Bzl),

Cha, D-Cha, Ser (Bzl), Tyr (Bzl), D-Tyr (Bzl), Nal, D-Asp (Bz I), His, Π-II,

G.lu (Bz.l), or D-Glu (Bzl), Tyr (Bzl) or (4-N0 ₂₎₎ - Phe, preferably Phe, CH

Tyr, Nal.,

Dn and En independently of one another are Ala, Gly, Pro, Asp or Thr or their O-form, preferably Pro, D-Pro, Ser or D-Ser,

Ser, Asn, Lys, D-Ala, Gly,

En is Gly, Asp or Asn or

Dn and En together are the AM-inokyseI the new v.zorea radical -NH- (C · ^) ^_ 2-5 lempl C0- or a peptide, preferably Btu, Clg, and the Trc or the D-EH LORM, in particular D -Biu.

Gn or Kn are independently πει self, D-ε, Met, D-Met, No, DN.le, Leu, D-Leu, Val or D-Val, preferably ε, Met, No or Leu, lln is IIOOC - (CII2) 4-CII (NH) -CO-, D-forms of this residue, Gly, Ala, D-Ala, Asn, D-Asn, Phe or D-Phe, preferably Asp, Glu or Gly,

An means

a) -AJ-A2-A3- wherein

A | is A.I or, Gly, Phe, I, I, 11e or its D-lane, preferably Gly, či1 or D-Ala,

Λ ₂ is the residue of ω-anionic acid of formula II, where n is 2, 3 and I or 5,

Λ ₃ is Phe, D-Pbe, 4-N () ₂ -Pbe, 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),

II is or D-III, preferably Phe, Tyr, Cha, Nal (4-NO ₂ ) Phe, or

-λ ₄ -λ ₅ - , where ^Λ 4 is a the remainder -am i nokyse1 i n of formula I I, wherein n is a 2, 3 or 5 ^Λ 5 is a Phe, D-Phe, 4-NO ₂ -h, Cha, l) -Cha, Sc r (Bz 1), D-S er (Bzl); Tyr, D-Tyr Ty r (Bzl), D-tyr (Bzl), Nal , D-Nal, Ibi, D-Thi, Asp (Bzl), D-Asp (Bzl) II i p , D-llis, Glu (Bzl) but : bo D-Glu (Bzl) Phe , Tyr, Cha, Nal or (4-NO ₉ ) -Pbe,

or

c) an anion of the formula III wherein iu is 1, 2, 3 or 4 and R is as defined in claim 8 when X is hydrogen, unsubstituted or chlorine, methoxy or (C1 to C3) an alkyloin substituted henzoyl radical, an cyclohexyl or methyloxycarbonyl radical, an unsubstituted or methoxy, nitro, trifluoromethyl or cyano substituted benzyloxycarbonyl radical, preferably a benzyloxycarbonyl, 4-methoxybenzyloxy-2-carboxy or 4-trifluoromethylbenzylcarbonyl, in particular benzyloxycarbonyl I., 4-nitrobenzyloxycarbonyl. 1 and / or 2- or 4-trifluoromethylbenzyloxycarbonyl, in particular benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or 2- µmol

4-trifluoromethylbenzyloxycarbonyl I,

Y represents a Cl already C1-4-allyl residue or (a C1 C1-4-alkyl) -phenyl radical, preferably benzyl or a phenyl I ethyl, and

X 1 represents phenyl or mono- or di-substituted phenyl, 2-pyridyl, 2-pyrazinyl, 3-benzo [b] phenyl or 2-naphthyl, in particular where:

means -Λ | -Α ₂ -Α ₃ -, where ^And 1 is Gly, ^A 2 J ^e Aea, pAlii, Apen, Abut , Gly or means only you bond and And ₃ is Phe, Phe (4-NO ₂ ), Tyr or Tyr (Bzl) or

An represents the group -A4-Λ3-, where

A4 is c βΑΙ.α, Aea, Tbc, Aund, B here or D-B here and

A 1 represents a covalent bond, Phe, D-Phe, Phe (4-NO ₂ ), Tyr,

Tyr (Bzl) or Cha or

An means um i nokyse I i. a new residue of formula III

-NH- (Cl ₂ ) _in -CH (R) -CO-, wherein m is I or 4 and R is -NHX, wherein II is H, Z, Bz, Henoe, (4-No ₂ ) Z, Tos , is or An is X - Lys -, kile 2

X is one of the following groups

() -

Ο

Preferred are the cyclopeptides of formula Ia

-A 1 -A 2 -N-Bn-Cn-In-En-In-Gn-II-I 11-K11 (Ia) and salts thereof, wherein:

A ₂ j Aund,

Aca, p-Ala

Ápen,

Abut or

Gly or metal bond,

A ₃ is Phe,

Pbe (4N0 ₂ )

Cha,

Tyr or Tyr (Bzl)

Bn is Arg,

Cn j e Phe,

Cha,

Ty alebo or Ty r (Bz1),

Dn is D-Ala,

Pro or D-Pro

En is Gly or

Dn and En together form β-Ala,

A hu t,

AOE

L-CKG,

L-B here or l or

Fn is Arg or Lys.

Gen. is a Ile, Me t, Aib or Not , H n is a Asp or AIB, I n is a Arg, Kn is a í le a ^A 1 is a Gly.

Especially preferred are the cyclopeptides and optionally one of the salts wherein A ₂ is _; and a new residue of the formula

-NH- (Cl ₂ ) ₂ - ₄ -CO-,

A ₃ is Pbe, Ty r, Cha, Na I or 4-NO ₂ -Phe,

Bn, Fn and In, independently of each other, are Arg, III, Alg, Lys,

D-Lys, Orn, or Ctr,

Cn is Pbe, Cha, Tyr, Na I or Tyr (Bzl),

Dn is D-A la, Gly, Pbe, or D-Pbe,

En is Gly or A1.1 or or

Dn and En together form D-B here,

Gn and Kn are independently white, met, No or Leu,

H n is Asp, Glu or Gly a

I is Gly, A I and or D-A Ia, especially those where

- 19A ₂ is β-Ala,

Apen or Abu C,

And ₃ is Phu,

Phe (4-NO ₂ )

Cha or Tyr.

Bn is Arg,

Cn j e Phe,

Cha,

Tyr or Tyr (Bzl)

Dn is D-Ala,

En is Gly or

Dn and En together form D-Btu,

Fn is Arg or Eys,

Gn j e 11 e,

Met or No,

Hn is Asp,

In is Arg,

Kn is I, Ie, and ^A 1 ^e j Gly.

Particularly preferred compounds of the invention are:

| -βα Ia-Arg - Phe-phi-AI aG I y-Arg-II e - A sp - A rg-II e -Aea-Arg-Phe-DA Ia-Gly-Arg-I le-Asp-Arg Ie-I βΛΙa _{Γ-Phe-Arg-Phe-D-A1a-yl} GI-Arg-Ile-Asp-Arg-Ile-Phe-Aea-A rg-D-Phe-Gly-Λ I a-Arg-I 1e-Asp-Arg-Ie-βΑ Ia-Phe-Arg-Phe-I) -A 1 aGy-Arg-II c-Asp-Arg-1e-Gly-Phe (4-NO2) -A rg-Phe-D-Ia-Gly y rg-Ie-Asp-Ag-Ie-Gly. r-βα 1α-Phe-Arg-Pbe-D-β I α-γ-Arg-Me-spsp-Arg-II eG I γ8. - βΑl α-Cha-Arg-Cha-DA I aG J y - Arg-Ile-Asp-Arg-II eG I y 9.

pAla-Phe (4-NO2) -Arg-Phe-D-Ia-Gly-Arg-Ile-Asp-Arg-Ile-Gly -

10th

_y Palau-Pbe (4-NO2) -Arg-Cha-D-Ala-Gly ΛIa-Arg-Ile-Asp-Arg-Ile-Gly. j — p Λ a-Tyr-Λrg-Cha- D-AI aG I y-Λrg - II e-Asp-A rg-I le-Gly

12. -pAla-Tyr (BzI) -Arg-Cha-D-Ia-GI-Arg-Ile-Asp-Arg-Phe-GI

-Aca-Phe-Arg-Pbe-pAla-Arg-Ie-Asp-Arg-Ie-GIyr-Aca-Phe-Arg-Abu-t-Arg-11e-Asp-Arg-Ile-Gly -

-Apen-Phe-Arg-Phe-D-Λ 1a-Gl-Arg-1 1 e -Asp-A rg-I le-Gly -Abu C -Phe-Arg-Phe-D-Λ 1a-Gly-Arg-1 1 e-Asp-A rg-1 1 e-Gly- -Gly-Phe-Arg-Phe-D-A1a-Gly-Arg-11 E-Asp-Arg-11 e-Gly

ρβΑ Ιa-Arg-Phe-D-A Ia-Gly-grg-I le-Arg-Ile-Gly-Aca-A rg. Phe-DA Ia-GIyArg-Ie-Asp-Ag-Ie-GIy-Aund-Arg-Phe-DA Ia-GIy-grg-Ic-Asp-Agg-Ie-GI yη

-Aea-Phe-Ag-Phe-Aoe-Ag-Ile-Asp-Agg-Ie-Gly-βΛI a-Phe-Ag-Phe-D-IΛ-GI-Arg-A h-Asp-Arg-Ie-GI y-Phe-Ag-Phe-DA Ia-GI y-rg-Ie e-h hA rg-IeG I yp βΑΙα-Phe -Arg-Phe -LB U u -Arg-I le-Asp-Arg-I le-Gly-,

25.-.beta.-.alpha.-Phe-Arg-Phe-D-Blu-Arg-11 le-Asp-Arg-11 le-Gly-

26th -βΑ1 α-Phe-r rg-Phe-P ro-G1 γ-Arg- II-Asp-Arg-11e-G-y-j 27 Mar: -Pal-Phe-Arg-Phe-D-Pro-Gly-N g-11e-Asp-Arg-11e-G 1y- | 28. -Tyr-Arg-Phe-D-a1a-Gly-grg-11e -Asp-Arg-11e-G1-y- 29th _r Tyr (Bzl) -Arg-Phe-D-a1a-G1y-Λr g - 11e-Asp-Arg- 11e-G'l- 30th -Phe-A rg-Tyr-D-A 1a-Gly-A rg-11e Asp-Arg-Gly-1LE 31. - Phe-Arg-Tyr (Bzl) - D-Λ 1a-Gly-grg-11e-Asp-Ag-11e-G 1y 32nd - β Ala-Phe-A rg-Phe-L-C.I.g-Arg-1 1 E-Asp-Arg-Gly-1LE 33. pβΛΊa-Phe-Arg-Phe-D-Λ 1a-Gly-A r g-N 1 e-Asp-Arg-I le-Gly-

as well as their salts

Preference is given to the formula I opeptides of the formula Ib

-A ₄ -A g-Bn-Cn-1) n-En-Fn-Gn-11 n-I n-K to their salts, where

A4 is Aund,

Aca, β-A 1a,

Clg, Tlie, Blu or D-B t. u.

A ^ is Phe, D-Phe,

Phe (4-NO ₂ )

Cha,

Ty r,

Tyr (Bzl) or just another bond,

Bn is Arg,

D-Arg,

C.tr.

Lys or metal bond

Cn is Phe,

Cha,

Ser (Bz 1) and Iebo Tyr (Me)

Dn is D-A I a,

Gly or Az t,

En is Gly,

Fn is Arg or Lys,

Gn j c 1 I e, D-I I e,

Met or No,

Hn is Asp, D-Asp,

Gly or a covalent bond, 1n is Arg or D-Arg and

Kn is clay.

Especially preferred are the cyclopeptides and possibly the salts thereof, wherein

A ₄ is a new residue of the formula

-NH- (C1-4) 2-4 -CO- or if I is a metal bond only,

Clg, Tbc, B here or D-B here, is Phe, Tyr, Cha, Na I or 4-NO 2 Pbe,

Bn, Pn and ln are independently Arg, D-Arg, Lys, D-Lys,

Orn or Ctr,

Cn is Phe, Cha, Tyr, Na I or Tyr (Bzl),

D 1 is D-Ala, Gly, Phe or D-Phe,

En is Gly or čiI or or

Dn and En are together D-Btu,

Gn and Kn are independently Ile, Met, Nie or Leu and

Hn is Asp, Glu or Gly, especially those where

A4 is β-Ala,

Apen or

Abut or when A 1 is a covalent bond is Clg, Tbc, B here or D-Btu

And ₅ is Phe,

Phe (4-N0 _2),

I want or Tyr or

Bn is a Arg, Cn Phe, Ch Chi, Tyr or Tyr (Bzl) Dn is a D-A l.a, En is a Gly or Dn and I 2n together Fn is a Arg or Lys, Cn is a Ile, Met or Not H n is a Asp, I n is a Arg a

Kn is clay.

2Ί

Preferred compounds of the invention are:

Ί -Aund-Phe-Arg-Phe-D-A1a-Gly-Arg-I 1e-Asp-Arg-1 le-Gly Second -Aca-Phe-A rg-Phe-D-a 1 a-G 1 y-A rg-I 1 e -As p-A rg-I 1 e-Gly - ³ - 1 -Aca-Phe-A rg-Phe-D-A 1a-Gl-Lys-I 1 E-Asp-Arg-I1 e-G l y -

4. r pA1 a-Phe-A rg-Phe-D-B tu-Λ rg-Ie-Asp-r rg-Ie-G I y2Κ

5. -βA I-Pbe-Arg-Pbe-DA I aG 1y -Lys-N Ie-Asp-Arg-Ie 6. -βΛΊa-Pbe-Alg-Se 1 (Bz I) -D- Λ Ia-Gly-Lys-N Ie-Asp-A 1g-I I e-

7th -Aca-Pbe-Lys-Phe-D-A'a-G-y-Arg-Ile-Asp-Arg-Ile- ⁸ -Aca-Pbe-Lys-Pbe-D-A 1a-Gl-Lys-Ile-Asp-Arg-1le- 9. -Aea-Pbe-A rg-Cba-D-a 1 α-G y-A rg-11 e-Asp-A rg-11 e- 10th -Aca-D-Pbe-Arg-Phe-D-A1a-Gly-Arg-J 1e-Asp-Arg-1 1 e 11. -Aca-Cba-Al-Phe-D-Al-1a-G-1-Arg-11e-Asp-Ag-11e-1 12th npAla-Pbe-Arg-Cba-D-A1a-Gly-Arg-11e-Asp-Arg-11e - 13th - p A 1 a - Pbe-A rg-Cba-D-Λ 1 a-G 1 y - A rg - Met: - Asp- A rg-1 1 e - ¹⁴ - pA 1a-Pbe (4-NO 2) -Arg-Pbe-D-Λ 1a-Gly-grg-11e-Asp- A r , Fifth - PAla - Pbe - Lys-Cha-D-a 1 a-G 1 y-Arg-11 e-Asp-Λ g - I 11:

I.

17th

.

19th

20th

.

22nd

23rd

2.4.

.

26th

-C1.g-grg-CIa - D-Λaa -Gly-Λrg-Ie-Asp-grg-Ie -

β-α-Phe (4-NO 2) -Arg-Cha-D-Λ 1a-Gly-Arg-Ile-Asp-Arg-1le- r p A la-Ty r (B /. 1) -Arg-Cha-D-a 1 α-G 1 y-Arg-11 e-Asp-A r g - I le-- p P A'l.a-Tyr - A rg-Cha-D-Λ 1 a-G 1 y - A rg-1 le-Asp-Arg - 1 le- ₁ -The-Arg-Cha - D-. L.a-G 1 y-Arg - 11 e-Asp-A rg - 1 1 e- - P A 1.a - Phe-C 1 -Cha-D-a 1 α-G 1 -Arg-1 le-Asp-Arg - 1 le- -The-Phe- and rg-Cha-D-A 1a-Gy-Λ rg-- 1 1 e-Asp-- A r g- 1 I.e - -C 1 g-A g-Cha-D-A 1 a-Gly-A g-I le-Asp-Arg-I e- [Beta] -Aund-Arg-Phe-D-A1a-Gly-Arg-11e-Asp-Arg-11e - -Aund-Phe-Arg-Phe-D-A1a-G1-Arg-I le-Asp-Arg - I I e- - Aeti -Arg- Phe - D-Λ 1 a - G 1 y - Lys - N 1 e-Asp-A rg - 1 1 c -

i.

rAca-grg-Se r (Bz I) -1) -Ia-Gly-Lys-Nle-Asp-Aleg-Ile28.

i-Aea-Phe - Arg-Phe-D-a a-G γ-l.ys-N Ie-Λ Λ g-Ie29.

pAl.a- Phe-A rg-Phe-D-Ia-Gly-Lys-N Ie - A rg-I e-j

30th

-Aca-Arg-Phe-D-Ia-Gly-Lys-N Ie-Arg-I e31.

i-pAl.a-A rg - Phe-D-Ia-GI-Lys-NIe-grg-1 I e

32nd

, -βα I-Phe-Gly-Se (Bz I) -D-Ia-Gly-Lys-Nle-Asp-Arg-Ile33.

i-Aca - Phe-G I y-Ser (Bz I.) -D-A I a-G l y-Lys-N I e-Asp-A rg-1 1 e-i

34th

-pAl.aG I y-Ser (Bz 1) -D-a I aG I y-Lys-N Ie-Asp-Arg-IIe ₃

35th

i-Aca-Gly-Ser (Bz 1) -D-Ia-Gly-Lys-N le-Asp-A.rg-Ie

36th

-pA I α-Ser (Bz I) -D-β I -Gly-Lys-N 1 e -Ap-Arg-I e e.

37th

i-Aca-Ser (Bz I) -D-A1a-Gly-Lys-Nle-Asp-Arg-Ile-i.

- B tu-Λ rg - Plic - Ι) - Λ I and -G I y-Λ rg- I - e - Asp - g rg - I c c 39.

- D-B tu-A rg-Phe-D-a a-G γ-A rg-I e-Asp-A rg-I e40.

P (J Ala-Arg-Phe-D-ΛΊ a-Gy-Arg-11e-Arg-Ie e.

Aca-Ag-Phe-D-Ia-Gly-Ag-Ie-Λrg-I e42.

, -pAla - Phe-Arg-Phc-D-A1a-Gly-Arg-Ile-Asp-Ag-B tu43.

-Aca-Phe-Arg-Phe-Ι-Λ a-G I y-g rg-I e-G y y-A rg-I c44.

.

.

j-Aca-Phe-A g-Tyr (Me) -D-Al a-G yy-fg-II e-Asp-A g-I I e-

-Aca- Phe-Arg- Phe-D-Λ 1a-Gl-Arg-D-11c-Asp-Ag-11c-j -Aca-Phe-A-g-Phe-D-A 1a-Gl-y-A-g-II-D-Asp-A-g-II e-

47th

.

-Aca-Phe-D-A Rg-Phe-D-A Ia-G1y-Fl-I 11 j-Asp-A rg-1 1 - ‘J F -Aca-D-Phe-A rg-Phe-D-A 1a-G1 y-A rg-I 11 -Asp-Arg-11 e- and

and salts thereof.

Preferred are the cyclopeptides of the general salt form, wherein

An is H-Lys,

Z-Lys,

Bz-Lys,

Henna-Lys, (4-N0 ₂₎ Z-Lys,

Bz-D-Lys,

Tos-Lys,

H-Dap ti I eho Z-Dap,

Bn is Arg,

Lys ,,

Phe or Orn,

Cn j e Phe,

Cha or Sei (Bzl)

Dn is D-Ala,

En is Gly or

Dn and En together form L-Clg or D-Clg,

Fn is Arg or Lys,

Gn is White or No,

I and theirs

Hn is Asp,

In is Arg and

K n j es.

Particular preference is given to cyclic opiates or their salts,

N is am inoa lkaIkyseI and a new radical of formula -NH- (CH _{2) R)} CH (R) -CO-, wherein n is 1 or 4, R is NHX or NXY.

X is benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2- or 4-trifluoromethylbenzyloxycarbonyl, cyclohexylcarbonyl I or methoxycarbonyl I and Y is benzyl or phenylethyl,

Bn, Fn and In are independently Arg, D-Arg, lys, D-Lys, Orn, and / or Ctr, wherein

Cn is a Phe, Cha, Tyr, Na 1, Tyr (Bzl) or 4-NO ₂ -Phc, D n is a D-A I i and, Gly, Phe ; or D-Phe, En is a Gly, Ala or Phe or Dn and En creates a spo 1 u D-Btu, L-Clg, or D-Clg, Gen. and! K n s ú does not matter with 1 e wearing Me, Me, Ne, and Leu and H n is a Asp, Glu or G l.y, naj mä t i e, where An is a I I-Ly: with , Z-Ly: WITH,

Bz-Lys,

Menocal-Lys, (4-N0 ₂₎ Z-Lys, D-Lys BZ-, Bz-D-Lys,

Tos-Lys,

I

- 35 ΙΊ-Dap or Z-Dap,

Bn is Arg, Lys, Orn, or Phe,

Cn is Phe,

Cha or Ser (Bzl)

Dn is D-Ala,

En is Gly or

Dn and En create them together

L-C.Ig or D-Clg,

Fn Arg or Lys, Gen. I le and 1 e Ix> N.l e, 1 H n JTJ Asp, 1 n j ľ Arg and

Kn is clay

Advantageous also according to the invention are:

1. H-Lys-Arg-Phe-D-Ala-Gly-Lys-NIe-Asp-Arg-Ile-

Second Z-Lys-Arg-Phe-D-Ala-Gly-Lys-Non-Asp-Arg-1le1 Third Z-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile- 4th Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-N1E-Asp-Arg-Ile- 5. Z-Lys-A.rg-Phe-D-Ala-Gly-Arg-11e-Asp-Arg-11e-i 1____ 6th Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-11e-

. Menne - Lys - r rg - Phe - Ι - a a - G y y - a rg - I e - Asp - r rg - I e e 8. Menne-Lys-A-g-Cha-D-A-a-G.I-A-g-Ile-Asp-A-g-Ile9. II-Lys-Lys-Cha-D-Λ 1 a-G Iy-A rg-I e-Asp-A rg-I I e-

10. Z-Lys-Lys-Cha-D-Λ 1a-Gly-Λ rg-11e-Asp-r rg-11e 11. Z-Lys-Phe-Phe-D-A1a-Gly-Arg-11e-Asp-Arg-11e1 12. (4-N0 ₂₎ Z-Lys-Λ rg-Cha-D-1 and G Λ 1 Λ y-rg-1 le-Asp-Arg-I, c-i 1_ 13. Z-Lys-Orn-Cha-D-A1a-Gly-Il-11e-Asp-Arg-Lle- 14. H-Lys-A rg-Phe-D-A1-a-G.I-Lys-N. 1 e-Asp-A rg-1 e- 1 5. II - Lys-grg-Se r (Bz 1) - D-Λ 1 a-G 1 y - Lys - N 1 c - Asp - A rg 1 -lle- 16. Bz-Lys-A1'-Phe-D-11a-Gly-Lys-N1e-Asp-Arg-11e- 17. Bz-Lys-Arg-Ser (Bz1) -D-11a-G1-Lys-N1e-Asp-Arg-I 1 e1

18. Bz-D-Lys-A rg-Se r (Bz1) -D-1; i-Cl! 1 y -1 .y s - N 1 c - Asp-N g- ' c - 19th Tos-Lys-ΛΛg-Phe-D-Λ 1a-G1 y-Λg-11c-Asp-Λc g-llc- 20th H-Lys-Arg-Phe-L-C1g-Arg-Ile-Asp-Alg-1 Ie1 21. Z-Lys-A1g-Phe-L-C1g-A1g-11e-Asp A1g-11c1 22nd Z-Lys-Arg-Cha-L-C1g-Arg-Ile-Asp-Arg-1e1 23rd Z-Lys-Arg-Cha-D-C1g-Arg-11e-Asp-Arg-11c- 24. H-Dap-Arg-Cha-D-A1a-G.I-Arg-Ile-Asp-Arg- I 1 e- | 25. Z-Dap-Arg-Cha-D-AJa-G1-A-g-IIe-Asp-A-g- 1 1 e- |

how and how so.

Preferred are the cyclopeptides of the formula I salts wherein

An is as defined above,

Bn is Arg,

Lys,

Phe or Orn,

Cn is Phe,

Cha or Ser (Bzl)

Dn is D-Ala,

En is Gly laebo

Dn and En are together L-Clg or n-cig,

Fn is Arg or Lys,

Gn j e I e e or No,

Hn is Asp,

In is Arg and

K n j 'e ile.

and theirs

Particularly preferred are cyclopeptides or salts thereof, wherein

An is an aminoalkyl acid radical of the formula -NH- (Cl ₂ ) _n CH (R) -CO-, wherein n is 1 or 4,

R is - Nl l (H) - C (0) - Cl 1 ₂ - X ¹ -N (II) -C (0) OX ^-Cll2-1-N (II) -C (0) -X ¹ -N (II) -C (O) -CII = CH-X ¹ -N (II) -C (O) -O-Cl 2 -X ¹ , wherein X 'is a) Phenyl I, h) I or 2 substituents; substituted (I), (e) I- or 2-naphthyl, (d) 3-benzo [b] phenyl, (e) 2-pyridyl or (f) 2-pyrazinyl,

Bn, Fn and In independently of each other are Arg, D-Arg, Lys, D-Lys,

Orn and Iebo Ct r,

Cn is Phe, Cha, Tyr, Na I, Tyr (Bzl) or 4-NO7-Phe,

Dn is D-Ala, Gly, Phe, or D-Pbe,

En is Gly, Al and or Phe or

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

Gn and Kn independently of each other are Ile, Met, Nie or Leu and Hn is Asp, Glu or Gly, especially those where

N is -Nll- (CII _{2) 4} -CH (R) -CO-, wherein R is as defined above and Bn-Cn-Dn-e-Fn-Gn-m-H-chain is -Arg- To N- The Cba-D-Ia-Gly-Arg-Ile-Asp-Irg-I leak is illustrated in the examples

The compounds of the present invention are β-agons with thi. As natural ΛΝΡ exhibit

- specific and affinity binding to ANP receptors

- d. uric and saluric properties

- effectiveness in lowering blood pressure

- increasing hematos r i tu

- Increased levels of cyclic GMP (GMP: likely intra-human second messenger that can be detected in plasma in increased amounts after ANP administration)

- increased gomeomeric strength

- efficacy causing reaxiation of vessels

- broncho y is efficacy

- spasmophytic activity on smooth muscles, especially the intestines.

Said properties of the compounds of the invention were individually tested in the following ways:

- Binding to ANP-reeeptures

Binding to ANP-repertoires from zona-geromer The bovine downstream cell line was determined by the method of Burgisser et al. (Biochem. Bi.ophys. Res. Coinmun. 133, 1201, (1985)), modified according to Burgisser (2nd World Congress on Biology and Active Atrial Peptides, May 16-21, New York) Am Salt llypertens., Abstract B181, p 209 (1987)) with a commercial kilometer of AN AV A, Vangen, Switzerland.

- Reducing blood pressure, diuretic / saline wipes efficiency, rise in haem flux r i tu, rise in ... GMP

The experiments were carried out on chewed (Nemhulal ®) spontaneously hypertensive rats (Ivariovas). Tracea cannula. Blood pressure is registered from A.earotis via a pressure transducer (Statham) on a recorder (Valannabe Mu I ti eorde r) _; . The cardiac fraction is swollen 1a from the number of pulses in time-unit. Application of the substance is performed by cannula

IN . j ugu.l.a r i s. The bladder is cannulated with a small abdominal incision and urine is collected. The urine volume is determined by gravimellers. Sodium and potassium chlorine are determined by electrolysis. from arterial blood. Cyclic GMP is inverted and photometric,

Changes t ok r i. t ar te rl.l ne j Hamburg).

is measured by blood commercially available series of IOS (I BL,

- Effect on glomerular filtration

The filter rate glider is indexed on narcotized dogs by determining the inulin clearance by a standard method according to the wishes of the company. 33 (729, 1955).

-Relaxation of blood vessels

The effect on vascular relaxation analogous to ANP is determined by the moiety method of discomfort and shadow et al. (Eur. J. Pliarmaeo 1, 102, 169 (1984)). Rabbit thoracic aorta is reduced by supramaxial concentration of serotorin. 15 minutes after administration of the test substance, seroton-induced other contractions are measured compared to the control performed with the solvent. EC pl is plotted from several doses.

- Broncho l

According to the method of Konzette and Rossler (Areh.exper.Path. Pharmaeol. 195, 71 (1940)), aryan lagon and hence of new bronebospasms after i.v. administration of the test substance.

- Spasmographic activity on chicken chickens

According to the Curr.i.e-a et al. (Science, 221/4605, 71 (1983)), the spasmolytic activity against carbohydrate contractions on the chicken rectum was determined.

Administration of the compounds of the invention may be carried out intravenously, subculture, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, preferably by ionization or by literature known to enhance and orally. In animals of different species, there are doses that cause a significant decrease in blood pressure (> 2 <) mm lg) and / or diuresis (t-300%) or saluresis (+ 300%), as well as an increase in hematocrit (+ 3%) and cyclic GMP (+ 200%) between 1 µg / kg and 50 mg / kg. The dosages for bonachytic action in guinea pigs are in the same range. Binding teaches cell receptors zone g loma roux axis from bovine vessels 1 i if mol / l is achieved with IC med. 10 ¹⁰ and 1. 10 ⁵

The relaxing action on the aortic vessels is achieved with an ECc of between 10 &lt; -1 &gt; and the spasmographic effect in equal amounts.

on the rings of the king 1. 1 0 ⁴ mol / l. Koneenna chicken recti are

Since the β-receptor binding of the individual compounds of the invention as well as ANP both in the field and in the cortex well with biological effects, the identity of the mechanism of action among the natural is confirmed. peptides and compounds described herein. Therefore, it is also possible to expect from the compounds of the invention other features described for the biological properties of natural peptides that are not individually described herein.

The potency of the actions and compounds of the invention is comparable to that of ANP. An essential advantage of the compounds of the invention is their significantly smaller molecular size. It was not possible to deduce from the prior art that compounds with such a considerably smaller molecule size would have such satisfactory activity values. The synthesis of the compounds of the invention is substantially simpler and therefore cheaper than the synthesis of ANP or ANP derivatives of higher molecular weight that are similar to ANP.

The performance of the compounds according to the invention (especially in the case of tans of administration i) is considerably greater than that of ANP and ANP-like derivatives. The compounds of the invention, unlike ANP, contain no disultide bridges, which makes their metabolic stability against ANP and ANP-like derivatives better.

The following compounds are particularly advantageous because their ANP-receptor binding value (see assay for binding to ANP-receptors above) IC 50 is less than 5.10 µM.

and

-Aund-Phe-Arg-Phe-D-A1a-Gly-Arg-Ile-Asp-Arg-Ile-Gly- -Aca-Phe-Arg-Phe-D-Al-Gly-Arg-I le-Asp-Arg-Ile-Gly- -Aca-Phe-Ar-Phe-D-A 1a-Gl-Lys-1 1 e-Asp-A rg-11 c-G 1 y -

βΑΊa-Phe-rg-Phe-DB tu-ľg-Ile-Asp-Arg-11e-GIy-βΑΙ a-Phe-ľg-Phe-D-Λaa-GI γg-Ile-Asp -Arg-Ile-Gly-Phe (4-NO 2) -Arg-Phe-D-Λ 1a-GlyArg-Ie-Asp-Ag-Ile-Gly-β Ala-Phe-Ag - Phe - D - Λ I aG I y - A rg - Me ť - Asp - A g g- ΓΙ eG I y -i

-βα 1a-Cha-Arg-Cha-DA Ia-Arg-Ile-Asp-Arg-II eG I yi βΑ1 α-Phe (4-NO 2) -Arg-Phe-D-Λ I aG I ? -gg-Ile-Asp-Agg-Ile-Gly

-46r-BAla-Phe (4 -02) -Arg-Cha-D-Ala-Gly-Arg-11 le-Asp-Arg-Ile-Glyi-BAla-Tyr-Arg-Cha-D-Ala-Gly-Arg Ile-Asp-Arg-Ile-GlypflAla-Tyr (Bzl) -Arg-Cha-D-Al and -Gly-Arg-Ile-Asp-Arg-Ile-Glyp-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-, -QA1-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp -Arg-I le-Gly | ~ βΑ1 and -Phe-Arg-Phe-Pro-Gly-Arg-1 le-Asp-Arg-Ile-Glyj-BAla-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-Arg-GlypPhe-Tyr-D-Ala-Gly-Arg-Ile

Asp-Arg-Ile-Gly

-47 • Phe-Arg-Tyr (Bz 1) - D-Aa-Gly-Arg-Ile-Asp-Arg-Ile-Gly ·]

-Bala-Phe-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-Gly-.

i-BAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Nle-Asp-Arg-Ile-Glyr-BA 1 aArg-Phe-DA la-Gly-Arg-Ile-Asp-Arg -Ile f-Aca-Arg-Phe-D-Al and -Gly-Arg-Ile-Asp-Arg-I lepBAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg- Er ll-Aea-Phe-Arg-Phe-D-Al and -Gly-Arg-Ile-Asp-Arg-Ile.

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

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

-Aea-Phe-Lys-Phe-D-A1a-Gly-Arg-Ile-Asp-Arg-Ile-.

pAea-Phe-Lys-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-IleAca-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-11e-.

-43, -Aca-D-Phe-Arg-Phe-D-Al and -Gly-Arg -Ile-Asp-Arg-Ile-, -Aca-Cha-Arg-Phe-D-Ala-Gly-Arg- Ile-Asp-Arg-Ile-, r-βΑ 1 α-Phe-Arg-Cha-DA 1 α-Gly-Arg-1 le-Asp-Arg-Ile-i-BAla-Phe-Arg-Cha- D-Ala-Gly-Arg-Met-Asp-Arg-Ile

J.

j-βαla-Phe (4-NO 2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile j-βΑΙ a - Phe-Lys-Ch and D-A1 and -Gly-Arg-1 le-Asp-Arg-Ile.

J-GALA-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Tyr-IlepGAla (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile- Asp-Arg-Ile, j ~ BA1-and four-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Phe Fiala _{r-Ctr-Cha-D-Ala}

-Gly-Arg-Ile-Asp-Arg-Ile-Thc-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile3

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

-49-Aund-Phe-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-, -Aca-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg- Ile-, pAca-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile-, pBtu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp- Arg-Ile-D-Btu-Arg-Phe-D-Al and -Gly-Arg-Ile-Asp-Arg-IlepAca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Gly -Arg-1 le-iAca-Phe-Arg-Tyr (Me) -D-Al and -Gly-Arg-Ile-Asp-Arg-Ile-,

-Aca-Phe-Arg-Ph-D-Ala-Gly-Arg-D-Ile-Asp-Arg-Ile -Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-D-Asp- Arg-IlepAca-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-IlepAcá-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg -Ile-, i-BAa-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ilei-BAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile -Asp-Arg-D-Ile

-50Η - Lvs -Λr g-Phe-D-Λ1 and -G1y-Lys-N1e-A with p-Λ r g -11 e

Z-Lys-Arg-Phe-D-Al and Gly-Lys-Nle-Asp-Arg-1 le-i

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

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

Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Men-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-1le-i

Menoc-Lys-Arg-Cha-D-A1a-Gly-Arg-1-le-Asp-Arg-1-le

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

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

-51H-Lys-At. G-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-IleBz-Lys-Arg-Phe-D-Ala

Gly-Lys-Nle-Asp-Arg-Ile

B from -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.

I___J

Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-As p-Arg-IleH-Lys-Arg-Phe-L-Clg-Arg-1le-Asp-Arg-Ile-

Z-Lys-Arg-Cha-D-Clg-Arg-Ile-Asp-Arg-11le-.

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

(4-NO ₂₎ p ^ ZL-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile (4-NC> 2) Z-Lys-Orn-Cha-D-Al and G Ly Arg-1-le-Asp-Arg-1-le

-53s-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-

I í

j i

With respect to the spectrum of activity, the compounds of the invention can be used as antiphelicenzines, as by-potents, as diuretics, for improving blood flow (vasodi I and lactivity), e.g. vascular insufficiency for the treatment of cardiac insufficiency, coronary heart disease, crebrovascular insufficiency, renal insufficiency, pri; acute renal failure and edema of any origin, e.g. cerebral edema, also in cirrhosis of the liver, as a spasm, it counts on all smooth muscle organs, especially the gastrointestinal tract, including the bladder or urinary organs and the urinary tract .

Furthermore, they can be used for diagnosing the disease image and for testing the organ system. They can be used as adjuvants for the production of thi purification (aluminum chromatography) of the antibodies, optionally in receptor preparations as well as in immunoassays (eg RIA, ELI SA) and receptor binding assays (eg series ioreeeptor assay) as specific and selective ligands.

The invention also relates to the use of the compounds of the formula I as medicaments or pharmaceutical preparations containing them. It is preferred to use for humans.

For the preparation and treatment of the problem, efficacy is obtained from the process and, optionally, from other conventional dissolution aids, emulsifiers or other excipients, solutions, suspensions or emulsions are prepared. Suitable solvents are, for example, water, physiological saline solution or alcohols, for example ethanol, petroleum or glycerol, sugar solutions such as glucose solutions or murines here, or else mixtures of different solvents.

and

In addition, the compounds can be applied by implants, for example from polylactide, polyglycolide or polyhydroxy linoleic acid. Other application options are inhalation application, inhalation application (in the preparation, dosing aerosol, powder inhaler), tandem application (patch preparations, creams, ointments, gels, passive patches). efficacy may be enhanced by enhanccerem foam (and / or electric field (including ontophoresis)), oral administration (tablets, capsules, dragees, etc.).

The invention also encompasses the use of the compounds of formula I as components and intermediates in the aforementioned biochemical, bioteelines and immunoassays (produced by antibodies, affinity chronology, RIA, ELISA, radioneptor assay).

The compounds of the invention can be produced by generally known methods in peptide chemistry. These methods are described in Houben-Veyl, Methoden der organischen Chemie, et al. They are preferably produced by solid-phase peptide synthesis (e.g., G.Barany, RB Merriield in The Peptides-Anaysys, Biology, Vol. 2, 2-2X4 (19X0), Academic Press, New York or RC). Sbeppard, Int. J. Pept Res., 21, 1IX (19X3) or by other known methods, the protecting groups used are those described in Houben Vey I, Methoden. Preferably, urethane protecting groups such as fluorenylmethoxycarbonyl or tert-butoxycarbonyl are preferably used in order to avoid side reactions, whereupon groups in the amino acid side chains are additionally optionally present (see, for example, protected by suitable groups). houben-Veyl dial 15/1 or

TVGreene, Protective Groups in Organic Synthesis). Arg (NO ₂ ), Arg (di-Z), Arg (Pmc), Arg (M-1r), Tyr (tBu), Tyr (Bzl), Tyr (2,6-d iC I-Bz I) are used. ), Ser (tBu), Se.r (Bzl), Asp (tBu), Asp (Bzl), Glu (tBu), Glu (Bzl), His (Trt), Llis (Bum), Lys (Boc), llomo -Arg (M t '), llomo (Arg (' mc '),

Lys (Z), Z_Lys, Al (Boc),

Honio-A '(NO ₉ ).

For the synthesis of the compounds of the formula I by solid-phase synthesis, known resins based on polysyrene, polyacrylamide and polyether are suitable. For the synthesis of cyclopeptides, it is desirable to use anchored groups which, upon cleavage, give the peptide carboxylic acids. It is preferable to use anchored groups whose cleavage takes place under such mild conditions that the side chain protecting groups, if any, remain. Using I'moe-rase, such anchored groups are: 2-methoxy-4-alkoxybenzyl-alcohol groups (M. Merg.l.er et al., Proccdings of the 10 th American Peptide Symposium 1987, St. I.is, page 2.59 GG R: Marshal.l ed. Escoiii, Laiden (1988), Hydroxy.I ton i dome ty Iskoupi nti (II.Kunz, B.Dombo, Angew.Chem. I 27, 711 (1988)) or tri-1-benzoyl-1-carboxylic acid (II.Rink, P. Si eher, Pept ide 1988, p. 139). G. Jurig, E. Bayer Eds., V. Deryter, Berlin 1989).

Cleavage of the amino-protecting group is carried out in the case of the Bos group with trifluoroacetic acid in dichloromethane or, in the case of the Emoc group, preferably with an organic base, in particular amines such as e.g. or per morpholine in DME or N-methylpyrrole. Typical concentrations are 20 to 50% base in solvent, reaction time 10 to 120 minutes. The cleavage is preferably carried out in two steps, the first reaction time being about 3 minutes. The resin is then washed briefly with solvent. A further cleavage of 20% by weight in DME is carried out, then the solution is filtered off with suction and the resin is thoroughly washed with solvent. Preferred solvents for these wash steps are DME, NMP, dichloromethane, trichloromethane, methanol, ethanol, isopropanol, water and tetrahydrofuran. Upon complete removal of the peptide, the Fmoc-amino acid required for further coupling was added. This cycle is repeated until the desired resin-bound pepl.id is formed.

Methods known in peptide chemistry may be used for coupling (see art. Vey I., Methoden der organ I.schenn Chemie, vol. 15/2). Preference is given to using carbodiimides such as di-cyclohexylcarbodiimide, diisopropylcarbodiimide, ethyl 1- (3-dimethylaminopropyl) carbodiimide or O-thiazol-1-yl. y I te t frames for mercury iumhexafluorophosphate or tetrafluorohorate (R.Korror et al., THL, 1927 (198 * 1)) or henzoic acid I - I - y I -> xy - three s- ( di melamine (no) - f os Tort i umhexal Iorofos (t) (B. Castro et al., 1975, 1219). Addition of I - hydroxyhenzothiazole (IIOBt) or

3-Hydroxy-4-dioxo-3,4-dihydroxybenzof. The racemization can be promoted and the reaction rate increased if necessary. The amino acids Asn and Gln are preferably coupled in the form of their N-protected p-nitrophenyl esters. The coupling is usually carried out with a 2- to 5-fold excess of the N-protected amino acid and the coupling reaction is carried out in a solvent such as dichloromethane, dimethylformamide, N-methylpyrrolidone (NMP) or mixtures thereof. . The progress of the killing reaction is monitored by the Kaiser test (E. Ktier et al., Anal. B &apos; 34, 5 * 15 (1 * 170) or

TNBS test. In the case of incomplete acylation, the coupling is repeated until complete. Solid phase synthesis can be performed as manually as a j using a peptide synthesizer.

ry.l to i d (DPPA) a good synthesis

The peptides thus synthesized are finally cyclized by suitable methods described in the terra- ria. As the cycling reagents, reagents used for coupling amino acids such as pentafluorophenyl ester / DMAP and its diophenium phospho for the synthesis of compounds of formula I can be used for the synthesis of solid lazilyl-thrombocytes using the anchored 2-methoxybenzyl ethoxybenzenes. DCC / IIOBt-, DIC / HOBt- or TBTU methods are suitable for the generation of sequences. After the sequences have been formed on the resin, the N-terminal amino acid on the Fmoc group is conventionally cleaved, and the resin is thoroughly removed after pi-i.d. The reaction mixture was washed with diatomaceous earth and then treated with a 1% trifluoroacetic acid solution to cleave the peptide. Protecting the side chain groups of the peptide is retained. After the solvent has been distilled off, the peptides are reacted with a cyclization reaction, preferably a dihydrophase and i.dom, to the corresponding cyclopeptides. Thereafter, said side chain protecting groups are removed with a suitable cleaving agent. Trifluoroacetic acid / scavenger mixtures are preferred. The scavenger used is a substance such as, for example, α 1 of thiariol, cresol, incineration, n-thiol, water or the like, as well as mixtures thereof.

The peptides are then processed by conventional methods in peptide chemistry and purified.

Purification of the crude products obtained is carried out at midnight by gonograph chromatography on, for example, Scpliadd G25 (MR 1400) or G15 (MR 1400) 1% or 5% acetic acid.

If necessary, further purification is carried out by preparative RP-HPLC with methanol- or acetonitrile-water gradients with the addition of 1 to 2% trifluoroacetic acid.

Sephadex or polystyrene based cation exchange resins can also be used for purification.

The purification is preferably carried out by reverse phase IIPIC using water / acetone gradient with an addition of 0.1 to 0.2% trifluoroacetic acid. T

The purity of the compounds of formula I is tested by RP-HPLC. It also performs amino acid analysis on the ion exchange resin. (LKB), and by means of a gas chromatograph on a clear column no. Additional raccation control e. From this, ^ ³ C-NMR spectra (Bruker 400 Mllz) and FAB-mass spectra (Finnigan MAT 90) were recorded. Sequence determination is performed by sequencing m in the gas phase after tryptic cleavage.

The following examples illustrate the synthesis of the compounds of the invention without, however, limiting the invention in any way.

Examples of findings

Example 1

-βαla-Phe-grg-Phe-DA I aG IγArg-Ie-Asp--rg-Ile-GlySynthesis of peptides is performed on an ACT200 peptide synthesizer from Advanced ChemTech using Fmoc-tragedy using mod a controlled management program. A 50 ml shaking reactor was charged with 1 g of 2-methoxybenzyl ether resin from Baehem, Switzerland which was fed to a 0.5 mmole Fmoc-glycine cycle. Algae derivatives and amino acids are used. in: Fmoc-Ile-011, Pmoc-Arg (M tr) -OH, Ilmoe-Asp (tBu) -011, Fmoc-Gly-011, Fmoc-D-pha-OII Fmoc-Phe-OII and Fmoc-βΛ I and -OH. The coupling was carried out in each case with 3 equivalents of Fmoc amino-aminocyanine, 1-hydroxybenzotriazole and dicyclohexylcarbodiamide (coupling time 40 minutes). After the TNBS test is performed, it is incomplete in acylation. repeats the coupling using the same reagents and excess. In the case of incomplete acylation, the next cycle of the synthesis is started. The cleavage of the protecting groups was carried out with 20% piperidine in DMF (3 minutes, 15 minutes).

Between reactions, the resin is always washed 10 times. DMF. After the formation of the sequence 11 - βΑ I α - Phe - ,ry, (M tr) - β - I - D - a I a - (ϊ I y - Λ rg (M ΟΙ ΟΙ le-Asp (tBu) - Arg (ML r The resin is washed thoroughly with di-chloroformate and then 5 times with 20 ml of a 1% solution of trifluoroacetic acid in methanol at room temperature for a maximum of 10 minutes (until intense lilac color). The residue is triturated with ether, the ether is decanted, the peptide is dried under a stream of nitrogen and taken up in 130 ml of DMF, which has a pI value of about 8.5 with three thirds of amine. The solution is cooled to -20 and 0.2 g (0.75 mmol) of di-phenylphosphoroyl azide is added and the mixture is allowed to stand for 48 hours at -20 at 4. The pH is maintained for three weeks. The DMF is then removed in vacuo, the residue is triturated twice with ether, the ether is decanted and the residue is dried under a stream of nitrogen. The amino acid chain was removed with t.i.fluoroacetic acid (90/10) for 24 hours at room temperature. Evaporate the solution in vacuo, digest the residue with ether and purify through Dynamo x C. 18 hours.

Straight / µm column (10 x 2.14 cm) using gradients A: water / acetone / acetic acid to trifluoroacetic 95/5 / 0.2 and B: detto 20/80 / 0.2 from 10% A to 80% B in minutes, flow rate 20 ml, retention time 6.01 minutes. After freeze-drying, an amorphous colorless powder is obtained. FAB-MS (M-t-H) - 1360.5.

and sus i pep t i d

Example 2

-Aund-Phe-Arg-Phe-D-Ia-Gly-Arg-Ile-Asp-Arg-Ile-GlyS using Finoc-Aund-Oh instead of Fmoc-β-1 α-OII the crude peptide is obtained by postipip described in Example 1, which is purified under the conditions described for chromium togalate (5% to 80% B per 1 ml, retention time 7.45 minutes).

FAB-MS (M + H) &lt; + &gt; = 1473.2.

Example 3

-Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ic-Asp-Arg-Ile-GlyS using Fmos-Aca-OH instead of Fmoe-βΛIa-OH, the crude peptide is truncated according to the procedure of Example 1, which was purified under the conditions indicated for chromatography (5% to 80% B in 11 minutes, retention time 6.00 minutes). FAB-MS (M + H) &lt; + &gt; = 1403.1.

Example 4 p Aca-Phe-Ag-Phe-D-Ia-Gly-Lys-IIe-Asp-Ag-IeGIyS using Fmoc-Lys (BOC) -OH and Fmoc-Aca-01 -1 instead of Fmoc-βα-α-OII, the crude peptide was obtained according to the procedure of Example 1, which was purified by chromatography on the conditions described (5% to 80% B in 11 minutes, retention time 5.80) min).

FAB-MS (M + 11) + = 1374.9.

Example 5

-βαΙa-Phe-rg-Phe-DB tu rgg-Ile-Asp-rg-Ie-GIyS using Fnioc-DB tu-OII instead of Fmoc-DA I and -OII the crude peptide is obtained as described in of Example 1, which purified the chromatograph. in the described conditions (5% to 80%

B in 11 minutes, retention time 6.05 minutes).

FAB-MS (M + H) &lt; + &gt; = 1372.7.

Example 6

- (4-NO2) -Phe-grg-Phe-D-Ia-Gly-Λrg-Ile-Asp-Arg-Ie-GIyS using Pmoc-Phe (4NO2) -011 and without Fmoc-βΛ 1a-011, a crude peptide was obtained according to the procedure of Example 1 and purified by chromatography in the above-described potions (5% to 8 (1% B in 11 minutes, retention time 6.45 minutes)).

FAB-MS (M + 11) + = 1334.9.

Example 7

-βαΙ and -Phe-rrg-Phe-D-Λaa -Gly-grg-Me sp -Asp-grg-lle-Gly Alternatively, Pmoc-Me t-011 was also used and the procedure described in Example 1 was followed. to give the crude peptide, which is purified by chromatography as described (5% to 80% B in 11 minutes, retention time 6.10 minutes).

FAB-MS (M + 11) + = 1378.8.

Example 8

- βαΙα-Cha-rrg-Cha- D - a1αG γ -Arg-II e-Asp-rr-Ile-GlyS using Fmoe-Cha-OH instead of Pinoe-Phe-011 with the procedure described in Example 1 gives the crude peptide, which is purified by chromatography as described (5% to 80% B in 11 minutes, retention time 7.75 minutes).

FAB-MS (M + 11) + = 1373.0.

Example 9 _y Palau-Phe (4-NO2) -Arg-Phe-D-ΛIa-G1y-Arg-Ile-Asp-Arg-Ile-Gly,

Using Fmoc-Phe (4-NO2), a crude peptide was obtained as described in Example 1 and purified by chromatography as described (5% on BO% B in 11 minutes, retention time 6.50 minutes).

FAB-MS (M + H) &lt; + &gt; = 1406.2.

Example 10 p-Bα-Phe (4-NO 2) -Arg-Cha-D-Λaa-Gly-γ-γ-Asp-r-γ-I le-GlyS using Fmoe-Cha-OH and Fmoc - Phe (4-NO2) -011 gave the crude peptide as described in Example 1 and purified by chromatography under the conditions described (5% on BO% B in 11 minutes, retention time 7.40 minutes).

FAB-MS (M + H) &lt; + &gt; = 1412.0.

Example 11, -βα-γ-Arg-Cha-D-Ala-Gly-Al-Ig-Ile-Asp-Ig-Ile-Gly-

Using Fmoc-Tyr (tBu) -011 and Fmoc-Cha-OH, following the procedure described in Example 1, a crude peptide was obtained which was purified by chromatography. Under the conditions described (5% on BO% B per minute, retention time 6.40 minutes).

FAB-MS (M + H) &lt; + &gt; = 1383.2.

Example 1.2 ι-β-1 α-Tyr (Bz 1) -Arg-Cha-PA 1 α-Gγ-Arg-II e-Asp-Arg-II cG lγS using Fmoc-Tyr (Bz I) -ΟΙ 1 and Fmoe-Cha-OII as described in Example 1 gave the crude peptide, which was purified by chromatography under the conditions described (5% to HO% B per minute, retention time 8.50 minutes).

FAB-MS (M + H) &lt; + &gt; = 1473.2.

Example 13

s. ·

-Aea-Phe-Arg-Phe-β-1a-Ig-Ie-Asp-Ag-Ie-GlyS using Fmoe-Aca-OII and Li-β-I and-OII were obtained by the procedure described in Example 1 crude peptide which was purified by chromatography under the conditions described (20% to 80% B per minute, retention time 4.60 minutes). ;

FAB-MS (M + H) &lt; + &gt; = 1345.9

EXAMPLE 14 r-Aea-Phe-Arg-Phe-Ahu-Arg-11e-Asp-Arg-11e-Gly-.

J ---- _t f

Using Fmoc-Aea-OII instead of Fmoe-β-I a-OII and Finoc-Abu t-011, the crude peptide was purified as described in Example 1 and purified by chromatography as described (20%). to 80% B in 10 minutes, retention time 4.85 minutes). s

FAB-MS (M + H) &lt; + &gt; = 1373.8. !

ί i

I

Example 15

-Apen-Phe-Arg-Phe-D-Pha-Arg-Pha-Arg-Pha-Asp-Arg-Phe-Arg-III using Fiiioc-Apen-OII instead of Fmoc-βΛI a-OII with the procedure described in Example 1 gives the crude peptide which is purified by chromatography under the conditions described (20% and 80% B in 10 minutes, retention time 4.50 minutes).

FAB-MS (M + H) &lt; + &gt; = 1388.8.

Example 16

-A hu t: - Phe - Arg - Phe - D - aI aG ly-Λrg - IIe - Asp - rrg-Ie - GI y Using Fmoe-Ahu t-OH instead of Fmoc-βΛ I and The crude peptide was purified according to the procedure described in Example 1. chromatographically under the conditions described (20% to 80% B for 10 minutes, retention time 4.35 minutes).

FAB-MS (M + H) &lt; + &gt; = 1374.8.

Example 17 <-Gl.y-Phe-Ag-Phe-D-Al-a-G-y-A-g-1e-Asp-A-g-1e-G I y

Using Fmoc-G ly-OH instead of Fiiioc-β-I and -OII, the crude peptide was purified as described in Example 1 and purified by chromatography under the conditions described (20% to 80% B in 10 minutes, retention time 4.45 minutes). ).

FAB-MS (M + H) &lt; + &gt; = 1346.8.

I

Example 18.

[alpha] -Ala-Arg-Phe-D-Ia-Gly-Arg-Ie-Asp-Arg-Ile-GlyyS using the Fmoe-am inocyanine described in Example I gave a crude peptide which was purified by chromatography. Under the conditions described (20% to 80% B in 10 min t, retention time 3.25 min).

FAB-MS (M + H) &lt; + &gt; = 1213.8.

Example 19

-Aca-Ag-Phe-D-Ia-Gly-Ig-Ie-Asp-Ag-Ie-GIyS using Fmoe-Aea-OII instead of Fmoe-βΑ I a-ΟΙΊ is obtained by the procedure described in Example 1 the crude peptide which was purified by chromatography under the conditions described (20% to 80% B in 10 minutes, retention time 3.45 minutes).

FAB-MS (M + 11) + = 1255.8.

Example 20 A Aund-rrg-Phe-DA I aGlγ-Λrg-II e-Asp-Arg-Ile-GlyS using Fiiioc-Aurid-OII instead of Fmoe-βΑ I a-011 with the procedure described in Example 1 to give the crude peptide, which is purified by chromatography under the conditions described (20% nti% B in 10 minutes, retention time 5.15 minutes).

FAB-MS (M + 11) + = 1325.8.

66 Example 21 r-Aca-Pbe-A'g-Pbe-Aoc-A'g-11e-Asp-Arg-Ie-GlyS using Ilee-Aea-OII instead and Fmoe-Aoe-OII network as described above. in Example I, l'moe-β-Ia-OH, said crude peptide, which was purified by chromium toggle under the conditions described (5% to 80% B in 11 minutes, retention time 7.10 minutes).

FAB-MS (M + H) &lt; + &gt; = 1416.2.

Example 22

- βα Ia-Phe-rg-Pbe-DA Ia-Gly γg-βb-Asp-rgg-IeG IyS additionally using Fmoe-Aib-OII, as described in Example 1, yields a crude peptide which Purify the chromatographs under the conditions described (5% to 80% B in 11 minutes, retention time 5.70 minutes).

FAB-MS (M + 11) + = 1217.8.

Example 23 i-β Al. a - Pbe-Alg - Pbe-D-Ia-G I y-Alg - 11e - A i b-A rg-I e-G I y-.

Using Fmoc-A and b-Ol1 instead of Fmoe-Asp / tBu-OII, the crude peptide was prepared as described in Example I and purified by chromatography under the conditions described (35% per% in 13.5 minutes, retention time 3, 70 minutes).

FAB-MS (M + 11) + = 1330.9.

Example 24

-βαI-Phe-grg-Phe-LB mm-ΛΛg-Ie-Asp-Arg-Ile-GlyS using momoe-L-Btm-OII us in Vmoc-D-Ala-OH with the procedure described in Example I prepared a crude peptide, which was purified by chromatography under the conditions described (5% to 80% B in II minutes, retention time 5.90 minutes).

FAB-MS (M + H) &lt; + &gt; = 1372.7.

EXAMPLE 25 [beta] -α-Phe-Arg-Phe-DB [gamma] -Arg-11e-Asp-Agg-11e-GlyS using Fmoc-D-Btm-OII instead of Fmoe-D-Λ 1 a-OII with the procedure described in Example 1, a crude peptide is obtained, which is purified by chromatography under the conditions described (5% to 80% B in 11 minutes, retention time 6.05 minutes).

FAB-MS (M + H) &lt; + &gt; = 1372.7.

Example 24 i-βΑΙ. and - Phe-A rg - Phe-P r-G I y-f rg - I e-Asp-A rg - 1 le-Gly-,

Using Fmoc-Pro-OH instead of Fmoc-D-a I-OII, the crude peptide was prepared as described in Example 1 and purified by ehromatography in the described conditions (5% to% in 11 minutes, retention time 6.15 minutes). .

FAB-MS (M + H) &lt; + &gt; = 1386.8.

I

-βΛI α-Phe-Ig-Phe-D-Poly-Gly-Ig-Ile-Asp-Al-Ig-Ile-Gly-68 Example 27

Using Fmoc-D-Pro-OH instead of Fmoc-DA I a-OII, the procedure described in the example was purified to 80% B of fluorophore to 11 minutes, retention FAB-MS (M + 11) + = 1386 , the eighth

Example 28

-Ty rAg-Phe-D-Ia-GlyArg-Ile-Asp-Ag-Ile-Gly1 prepares the crude peptide id, which under the conditions described (5% for a time of 6.35 min. ).

With the additional use of Fmoe-Ty r (tBu) -011 and without Fmoc-β-I and-011, the crude peptide is purified as described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in II minutes, retention time 5.40 minutes). FAB-MS (M + 1) + = 1306.0.

Example 29

Tyr (BzI) -Arg-Phe-D-Ia-Gly-Arg-I Ic-Asp-Arg-Ile-Gly

With the additional use of Fmoe-Tyr (Bz1) -011 and without Fmoe-βΑΙa-OII, the crude peptide was prepared as described in Example 1 and purified by chromatography of the reagents under the conditions described (5% to 80% B). 11 min, retention time 6.10 min t).

FAB-MS (M + H) &lt; + &gt; = 1395.9.

Example 30

- Phe-A rg-Ty r -D-Λ Ia-Gly A rg-11e - Asp - A rg-IIe - (ϊ I y With additional use of Fmoc-Tyr (1'Bu) -OH and without The crude peptide was purified by chromatography as described in Example I (5% to 80% B in 11 minutes, retention time 6.55 minutes) as described in Example I.

FAB-MS (M + H) &lt; + &gt; = 1 305.9.

Example 31

-Phe-A rg-Tyr (BzI) -Da Ia-GIy--rg-11e-Asp-A rg-11eG IyS additionally using Fmoc-Tyr (BzI) -OH and without Fmoc-βΑΙ a-OII The crude peptide was purified according to the procedure described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in 11 minutes, retention time 7.10 minutes). FAB-MS (M + H) &lt; + &gt; = 1395.9.

Example 32 i-βΑΙa - Phe - A rg - Phe - L-C I g-A rg - I e-Asp- A g - I e -G I y ->

Using Fnioe-L-CIg-OH instead of Fmoc-D-III and -OII, the crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (5% to% B in 11 min, retention time 6). , 90 minutes).

FAB-MS (M + H) &lt; + &gt; = 1400.8.

EXAMPLE 33 i-βΑ 1 α-Phe-grg-Phe-D-aGaγ-Arg-N-e-Asp-rrg-II eG 1γS additionally using Fmoc-NIe-OII with the procedure described in Example 1 prepares the crude peptide, which is purified by chromatography as described (5% on BO% B per minute, retention time 6.40 minutes).

FAB-MS (M + H) &lt; + &gt; = 1360.4.

EXAMPLE 34 [beta] -Ala-Phe-A1: g-Cha-D-[alpha] -Gly-Arg-Me-Asp-A-g-Ile-.

Peptide synthesis is accomplished using Advanced GhcmTech ACT200 peptide synthesizers using Fmoc-s tralgis using a modified control program. 50 ml shaker. The reactor was charged with 1 g of 2-methoxybenzyl ether resin from Baehem, Switzerland, which was fed into a 0.5 mmole Fmoc-1 / iucine cycle. The following amino acid derivatives were used: Fmoe-(rg (M r r) -011, Fmoc-Me t-011,

Fmoc-Asp (tBu) -OH, Fmoc-Gly-OH, Fmoe-D-Ia-011 Fmoe-Cha-OH and Fmoc-βΑ I a-OII, Fmoc-βΑ I a-011. Coupling is carried out with 3 equivalents of Fmoc-amino acid, 1-hydroxydenzoyltriazole and dicyclohexylcarbonide (coupling time 40 minutes). Following the TNBS assay, coupling with the same reagents or excess is repeated in the case of incomplete aeylase. In the case of incomplete acylation, the next synthesis cycle is started. Cleavage of the Fmoc-protecting groups is performed with 20% buffer in DMF (once for 3 minutes, once for 15 minutes). Between the reactions, the resin was washed 10 times with DMF. After forming the sequence H 1 Al.a-Phe-Arg (Mtr) -ChaD-Ala-Gly-Yγg (M tr) -Met-Asp (t Bu) -Arg (M tr) -Effective Polymme The carrier is rinsed thoroughly with dichloromethane or thereafter

5 times 20 ml each. Of a 1% solution of the acid at room temperature for a maximum of 10 microns (up to the intense main color of the resin). The solutions were combined and stripped under vacuum. The residue is triturated with ether, the ether is decanted, the peptide is dried under a stream of nitrogen and taken up in 1.30 ml of DMF, the pH is adjusted to about 8.5 times and the solution is cooled to -20 and 0, 2 g (0.75 mmol) of diene I-20 [deg.] C., suitable for 8.5. smear with e ery lazid du. The mixture is left to flock for 48 hours at 4. The pH is maintained with triethylamine, DMF is removed in vacuo, the residue is doubled, the ether is decanted and the residue is dried under a stream of nitrogen. The side chain protecting groups are cleaved with trifluoroacetic acid / anisole (90/10) in 24 hours. The solution is concentrated in vacuo, the residue is partitioned with ether and dried. The crude peptide was purified over a Dynamax C18, µm-column (10 x 2.15 cm) using Λ: water / acetone / tril / acid gradients to three fluoroacetic 95/5 / 0.2 and B: detto 20/80 / 0.2 from 10% B to 80% B in 11 minutes, 20 ml flow rate, retention time 7.80 minutes. After freeze-drying, an amorphous colorless powder is obtained. FAB-MS (M + H) &lt; + &gt; = 1327.9.

Example 35 βAla-Arg-Phe-D-A1 and -Gly-Arg-Π e-Asp-A rg-I I e

Using Fmoe-II e-Ol1 in place of Fmoe-Met-OH and without Fmoc-Cha-OH, the crude peptide was purified by the procedure described in Example I which was purified by eh roma migrations under the conditions described (20% to 80%). B over 10 min, retention time 3.25 min) FAB-MS (M + H) + = 1156.7.

Example 36 pAca-Arg-Phe-D-Ia-Gly-Arg-Ie-Asp-Ile-i

Using Fmoc-Aca-OII instead of Fmoc-IA-a-011 and Fmoc-Ile-OH instead of Fmoe-Met-OH and without Fmoc-Cha-OII, the crude peptide was obtained as described in Example 1 and purified by ehromatography in conditions described (20% to X0% B in 10 minutes, retention time 3.70 minutes)

FAB-MS (M + 1) + = 119X.X.

Example 37 pAund-Arg-Phe-D-Ia-Gly-Arg-Ile-Asp -Arg-Ile-i

Using Fmoc-Aund-011 instead of Fmoc-β-I a-011 and Fmoe-Ile-OH instead of Fmoe-Me t-OH and without Fmoc-Cha-OII, a crude peptide was obtained as described in Example 1, which was purified by chromatography under the conditions described (20% to X0% B in 10 minutes, retention time 5.55 minutes)

FAB-MS (M + H) &lt; + &gt; = 1268.9.

Example 3X, -Aca-Phe-Ag-Phe-D-Ia-Gy-Agg-11e-Asp-Agg-Ie-i

Using Fmoc-Aca-OH instead of Fmoc-β-I a-011 and Fmoe-I.le-OH instead of Fmoe-Me t-OH and without Fmoc-Cha-OII, the crude peptide was purified as described in Example 1 and purified chromatographically under the conditions described (20% to X0% B in 10 minutes, retention time 4.90 minutes)

FAB-MS (M + 11) &lt; + &gt; = 126X, 9.

Example 39 .beta.alpha.-Phe-A rg-Phe-D-Λ I aG I y-A rg-I e-Asp-A rg-I e e using Fmoe-1 I e-OII instead of Fmoe-Cha -OH, following the procedure described in the example for peptide purification of quartz crystals (20% to 80% B in 10 minutes, retention FAB-MS (M + H) + = 1304.0).

Fmoe-Met-OH and without the raw materials described above (4.50 minutes)

Example 40

P βΑΙα - Phe - A rg-Phe - D-Λ a-G γ-Lys-N I e-Asp-A rg-11 e-.

Using Fmoe-Lys (BOC) -OH and Fmoc-N I e-OII instead of Fmoc-Met-OII and without Fmoe-Cha-OH, the crude peptide was purified as described in Example 1 to be purified by chromatography. conditions described (5% to 80% B in 11 minutes, retention time h, 10 minutes)

FAB-MS (M + H) &lt; + &gt; = 1275.0.

EXAMPLE 41 [beta] - [beta] -1-Phe-Arg-Ser (Bz I) -I) -A [alpha] -Gly-Lys-N1e-Asp-Arg-Ie-i

With the additional use of Fmoe-Lys (BOC) -011 and Fmoe-Se r (Bz I) -OH instead of Fmoe-Cha-OII and without Ftttot-N 1 e-OII, the crude peptide is purified as described in Example 1 and purified chromatographically under the conditions described (5% to 80% B for 10 minutes, retention time 6.20 minutes)

FAB-MS (M + 11) + = 1.305.0.

EXAMPLE 42 pAca-Phe-Lys-Phe-D-Ph.a-Gly-Arg-Ile-Asp-Flu-Ile -,

Using Ilmoc-Aca-OII instead of Fmoc-βΛ I a-OII and Finoc-I le-OII instead of Fmoc-Met-OH and Fmoe-Lys (BOC) -011 without Fmoc-Cha-OH, following the procedure described in Example 1 to give the crude peptide, which is purified by chromatography under the conditions described (5% to 80% B in 11 minutes, retention time 6.60 minutes) FAB-MS (M + H) + = 1318.2.

Example 43 i-Aca-Phe-Lys-Phe-D-Ia-G1y-Ly s-1 Ie-Asp-Ag-1 Ie-

With the additional use of Fmoe-Lys (BOC) -011 and Fmoe-Aea-Ol-1 instead of Fmoe-βΑ I a-OII and Fmoe-Ile-OII instead of Fmoe-Me t-OH and without Fmoc-Cha-OH with the procedure described in the example I gives the crude peptide, which is purified by chromatography under the conditions described (5% ruthenium 80% B in 11 minutes, retention time 6.40 minutes) FAB-MS (M + H) + = 1290.2.

EXAMPLE 44 j-Aca-Phe-Ig-Cha-III-A1a-Gly-Ig-Ile-Asp-Arg-Ile- | T

Using Fmoc-Aca-OH instead of Fmoc-β-I a-011 and Fmoe.-I le-OII instead of Fmoe-Met-OH, a crude peptide was obtained as described in Example 1, which was purified ehromatographically under the conditions described (5% on 80% B in 11 minutes, retention time 7.35 minutes)

PAB-HS i ··! · !! ,, v, f 2

Example 45, -Aca-D-Phe-Arg-Phe-D-Ia-Gly-Ig-Ie-Asp-Ag-Ie-.

Using Fiiioc-Aea-OII es to Fmoc-β-I and-011 and Fmoc-II e-011 instead of Moc-Me M-OII and Imoe-D-Phe-011 and without Fmoe-Cha-OII with the procedure described in Example I yields a crude peptide that is purified by chromatography under the conditions described (5% to 80% B in 11 minutes, retention time 6.35 minutes) FAB-MS (M + 11) + = 1346.2.

Example 46, -Aea-Cha-Ag-Phe-D-Ia-Gly-Agg-Ic-Asp-Agg-Ic-.

Using Fiiioc-Aea-OII instead of β-I α-OII and Fmoc-I 1c-011 instead of Fmoc-Me t-011 and following the procedure described in Example 1, a crude peptide is obtained which is purified by chromatography in the described conditions (5% to 80% B in 11 minutes, retention time 7.35 minutes)

FAB-MS (M + 11) + = 1352.0.

Example 47 | - βΑΊ, α-Phe-rg-Cha-D-a a-G γ-γ-γ-γ-Asp-Arg-III-I

Using Fmoc-11c-011 instead of Fmoc-Mct-0H, following the procedure described in Example 1, a crude peptide was obtained which was purified by chromatography under the conditions described (5% to 80% B for 11 min, retention time 5.90 min) .

FAB-MS (M + 1) + = 1309.5

Example 4 '- βα Ia- (4NO2) Phe-Ig-Phe-D-Ia-Gly-Ig-Ie-Asp-Ig-Ie- With additional use of Fmoe- (4-NO2) ) Phe-011 and Finoc-I le-011 instead of Fmoe-Met-OII ti without Fmoe-Cha-011 yield the desired crude peptide according to the procedure described in Example 1, which is purified according to the conditions described above ( 5% to 80% B in 10 min, retention time 6.85 min).

FAB-MS (M + 11) + = 1348.9

Example 49 - βα 1α-Phe-Lys-Cha-Λ I and Gly-Arg-11e-Asp-Ig-11e- With the additional use of Fmoe-Lys (BOC) -OII and Fmoe- Ile-OH instead of Fmoe-Met-OII gave the crude peptide as described in Example 1, which was purified by ehromalography under the conditions described (5% to 80% B in 10 min, retention time 6.75 min) FAB-MS (M + H) + = 1281.9

Example 50

- C.1 g-grg-Cha- D-A1a-Gly-Agg-Ie-Asp-Arg-Ie -

Using Fmoc-C 1 g - (III) mixed Fmoc-Ala-OII and 1'mocI le-OH instead of Fmoc-Me t-011 and without Fmoc-Phe-OII, the crude peptide was obtained as described in Example 1, which Purify by chromatography under the conditions described (5% to 80% B in II nrin, retention time 7.35 min).

FAB-MS (M + H) &lt; + &gt; = 1259.8

EXAMPLE 51 βAla- (4NO 2) Phe-Arg-Cha-D-Al-Gly-Arg-Ile-Asp-Arg-IIc Using Fmoc- (4-NO 2) Phe-OII instead of Fmoc-Phe-OH and Finoc-1 le-OII instead of Fmoc-Me t -011 gave the crude peptide following the procedure described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B in 10 min, retention time 6.45 min) .

FAB-MS (M + H) &lt; + &gt; = 1354.7

Example 52

- p A la-Tyr (bz I) -Arg-Cha-1-Ia-Gy-Arg-Ic-Asp-Arg-Ie -

Using Fmoc-Tyr (bzI) -OH instead of Fmoc-Phe-OII and Fmoc-I le-OII instead of Fmoc-Me 1-011 gave the crude peptide as described in Example 1, which was purified by purification by chromatography to obtain a crude peptide. conditions (5% to 80% B in 10 min, retention time 8.20 min).

FAB-MS (M + H) &lt; + &gt; = 1415.9

Example 53

- pAla-Tyr-Arg-Cha-D-A'a-Gly-Al-Ig-Ile-Asp-Arg-11le -

Using Fmoc-Tyr - (BuBu) - 011 Fmoc-Ile-OH instead of Fmoe-Met-OH, Example 1 was obtained to obtain the crude peptide which was in the described conditions (5% retention time 6.45 min).

FAB-MS (M + H) + - 1325.8 in place of I'moe-Phe-OII and purification of ethanol and 80% B in 10 min as described.

Example 54

The-Arg-Cha-D-Ia-G-y-Arg-Ie-Asp-Arg-Ie e—

Using Finoe-THc-OII instead of Fmoc-β-Ia-011 and FIIiol-II.e-OH instead of Fmoe-Met-011 and without Fmoc-Phe-OII, the crude peptide was obtained as described in Example 1, which was purified by chromatography - fou under the conditions described (5% to 80% B in 10 min, retention time 6.45 min).

FAB-MS (M + 11) + = 1279.7

Example 55 _Γ -β A 1a - Phe - T r - Cha - D - a I aG I y - ľ g -1 le-Asp-Arg-I e -

With additional use instead of Fmoc-Met-OH, the crude peptide was purified by the procedure (5% to 80% B in 10 FAB-MS (M + 11) + = 1310.6).

The Fmoe-C t-011 and l'moe-I e e-011 na, described in Example I, were prepared by chromatography on the described minutes (retention time 7.00 min).

Example 56

- The-Phe--rg-Cha-D-a a-G y y-r rg-I e e-Asp-r rg-I e e—

Using Fmoc-The-OII Fmoe-Ile e-011 instead of Fmoe-Me t-011 Example T, the crude peptide was obtained, f.iou under the conditions described (5 retention time 7.60 min).

FAB-MS (M + H) + = 1426.7 in place of Fmoc-βΑI α-OH and purified as follows to% 80% opiate in chromagraB in 10 min,

Example 57 - Clg-Arg-Cha-D-Ala-Gl-Arg-11e-Asp-Arg-11e-

Using Finoe-C18-OII instead of Fmoe-βΛ I a-OII and Fmoe-Ile-OII instead of Fmoc-Met-OH and without Fmoe-Phe-011, the crude peptide was purified as described in Example 1 and purified

80 chromatography conditions described (5% to 80% $ 10 in 10 min, retention time 8.90 min). FAB-MS (M + H) &lt; + &gt; = 1406.7

Example 58-Acéi-Arg-Phe-D-Pha-Gly-Lys-N Ie-Asp-Arg-Ic

Additional use of Fmoc-Lys (BOC) -011 and Fmoc-Aca-OII in place of Fmoc-β-I a-0H and Finoc-N I e-011 instead of Fmoc-Me t-011 and without Fmoc-Cha-OH with the procedure described in Example I, the crude peptide was purified, which was purified by ethanol chromatography under the conditions described (5% to 80% B in 11 min, retention time 5.45 min). FAB-MS (M + 11) + = 1170.6

Example 59

-Aca-A g-Se r (BzI) -D-Ala-Gly-Lys-N Ie-Asp-A g-Ie e-

For use

Fmoc-Aca-011 nam i cs to lmoc- βΛ I a-OII,

Fmoc-N.l e-OII instead of Fmoc-Me t-OH ti Fmoc-Ser (Bz I) -011 instead

Fmoc-Cha-OH was the peptide obtained by the procedure described in Example I and was purified by flash chromatography under the conditions described (5% to 80% B in 11 min, retention time 5.70 min). FAB-MS (M + 11) &lt; + &gt; = 1200.5

-. 8 I

Example 60

- Aca-Phe-Arg-Phe-D-A Ia-Gly-Lys-N1 e-Arg-I le-

With the additional use of Fmoe-Lys (BOC) -OH Li-Aca-OII instead of Fmoe-β-1 α-OII and Fmoc-N I e-011 instead of Fmoc-Me t-011 and without Fmoe-Cha-OH thimoe-Asp (tBu) -011 gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B for 11 min, retention time 7.10 min).

FAB-MS (M + 11) &lt; + &gt; = 1089.5

Example 61

--βΑΙ. α-Phe-rr-Phe-D-a 1 α-Gly-Lys-Nle-A rg-Ile

Using Fmoc-Lys (BOC) -011 and Fmoc-N11e-011 instead of Fmoc-Me t-OII without Fmoc-Cha-Olli Fmoe-Asp (tBu) -011, the crude peptide was obtained as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B in II min, retention time 6.90 min).

FAB-MS (M + 11) + = 1160.6

Example 62

- Ac-A-g-Phe-D-Ia-Gly-Lys-N 1 e-A-g-I I e -

Using Fmoc-Lys (BOC) -011 and Fmoe-Aca-OH instead of Fmoe-βα-α-OII and Fmoe-Nl e-011 instead of Fmoe-Met-OII, the crude is purified by ehromatography without the procedure described in Example I. described at 80% B in 11 min, retention time 5.95 min)

FAB-MS (M + H) + = 1055.7 rmoc-cna-un with peptides which conditions (5%

Example 63

- βΛ.l.a-Arg - Phe-D-A I a-G I y - Lys - N I e - A rg-I I e—

Using Fmoe-Lys (BOC) -OH and Fmoe-N I e-OII instead of Fmoc-Me-OH and without Fmoe-Cba-OH and Fmoe-Asp (1Bu) -OH, the crude peptide was obtained as described in Example 1. Purification by chromatography under the conditions described (5% to 80% B in II min, retention time 5.90 min).

FAB-MS (M + H) &lt; + &gt; = 1013.6

Example 64

- βΑ l.a - Pbe-G I y-Se r (Bz I) - D-I a-G I y - Lys-N I e-Asp-Arg-I e -

Using Fmoe-Lys (BOC) -OH and Fmoe-Se r (Bz I) -011 n Fmoc-Nl.e-OH instead of Fmoc-Me 1 -OH and without Fmoe-Cba-OH was obtained as described in Example 1 crude peptide which was purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.85 min).

FAB-MS (M + H) &lt; + &gt; = 1206.4

Example 65 - Aea - Phe-Gly-Phe-I-A 1 a-Gly-Lys-N-e-Asp-A-g-I e -

Using Fmoc-Aca-OH instead of Fmoe-β-Ia-OII and ilmoc-Nl.e-OH instead of Fmoe-Met-OII and Fmoe-Lys (BOC) -OH and without Fmoe-Cha-OII, following the procedure described in the example 1 gives the crude peptide, which is purified by chromatography under the conditions described (5% to 80% B in 1 min, rt 7.40 min). FAB-MS (M + H) &lt; + &gt; = 1248.5

Example 66 - βαΊα-Gly-Se (B zI) -D-a-α-Gly-Lys-N-e-Asp-A-g-II

Using Fiiioc-Lys (BOC) -011 and Imoe-Se r (Bz I) -OH instead of Fmoc-Phc-011 and Fmoc-N le-011 instead of Fmoe-Met-OH and without Fmoe-Cha-OH with the procedure described Example 1 yields the crude peptide: which is purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 5.80 min).

FAB-MS (M + H) &lt; + &gt; = 1059.4

EXAMPLE 67 [beta] -Aca-Gly-Ser (BzI) -D-11a-Gly-Lys-N Ie-Asp-Ag-Ile] |

Using Fmoc-Aca-OH instead of Fiiioc - βΛ I α-Oli,

Fmoc-Ser (Bzl) -OH instead of Fmoc-Cha-OH and Fmoc-N le-011 instead of Fmoc-Met-OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% on 80% B in 11 min, retention time 6.20 min).

FAB-MS (M + H) &lt; + &gt; = 1101.5

Example 68

- βαΊ α-Se r (BzI) - D-Λ Ia-GI-Lys-N Ie-Asp-A rg-I I e—

Using Fmoc-Se ((Bz I) -OH instead of Fmoc-Clia-OII and Fmoc-Ie e-011 instead of Fmoc-Mc ť-011 and addition of Fmoc-Lys (BOC) -011 was obtained as described in Example I Crude peptide which was purified by chromatography under the conditions described (5% to 80% B for 11 min, retention time 6.05 min).

FAB-MS (M + 11) + = 1002.6

Example 69

-Aca-Se r (Bz1) -D-Aa-Gly-Lys-N-e-Asp-A-g-I-e: i

Zri use Finoc-Aea-OH in place of Fmoc-a-βΛ I, OH, II.e FINO-OH-ntimi.esto Fmoc-Met-011 and Ser-Fmoc (Bzl) -OH instead of Fmoc-Cha ² 0H, and Fmoc-Lys (BOC) -OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.60 min).

FAB-MS (M + H) &lt; + &gt; = 1044.5

Example 70

--Bu -Arg-Phe-D-Ala-Gly-grg-Ie-Asp-A'g-Ie e-

Using the Finoc-B tu-OII-III.e-OII instead of the Fmoc-Me t-OH described in Example 1, it is obtained by ehromatography at the described min, retention time 5.34 min). FAB-MS (M + H) + = 1225.6 instead of Fmoc-β-I and -OII and Fmoc-Cha-011 non-Fmoc-procedure, the crude peptide was purified by conditions (5% to 80% B in 11

Example 71

-D-Btu-Alg-Phe-D-Ala-Gly-Arg-Ie-Asp-Arg-Ie-

Using il-DB-u-011 instead of Il-1A I a-OII and Il-1 I-e e OII instead of Fmoc-Met-OII without il-Cba-OII, the crude peptide was obtained as described in Example 1. Purification by chromatography under the conditions described (5% to 80% B in 11 min, retention time 5.15 min).

FAB-MS (M + 11) + = 1225.6

Example 72

- pA.la-A rg - Phe - D-Λ I a-G I y-g rg- I 1 e - A rg - I I e - -

Using il-II e-011 instead of il-Me t-011 and without Finoc-Cha-OH and il-Asp (tBu) -OH as described in Example 1, a crude peptide was obtained which was purified by chromatography as described above. conditions (5% to 80% B in 11 min, retention time 6.15 min).

FAB-MS (M + H) &lt; + &gt; = 1041.5

Example 73

- Aea-A rg-Phe-D-Ia-Gly-A rg-I e-A rg-I I e—

Using Fmoc-Aca-OH instead of Fmoc-AA.I α-OII ti Fmoc-Ile-OII instead of Fmoc-Met-OH and without Fmoe-Cha-OH and Li-Asp (tBu), crude was obtained as described in Example 1 a peptide that is purified by chromatography on the described sub-fractions (5% to 80% B in 10 min, retention time 10 10 min).

FAB-MS (M + H) &lt; + &gt; = 1083.9

Example 74

-Aca-Phe-grg-Phe-D-Λ Ia-Gly-grg-I le-Gly-Arg-11e -

Using lmoe-Aca-OII-III.e-OH instead of Fmoc-Met-OH Sti 1, the crude peptide was obtained which was subjected to Strong conditions (5% to 80% B min).

FAB-MS (M + H) &lt; + &gt; = 1331.2

EXAMPLE 75 Instead of Fmoc-β-Ia-OII, by the procedure described in the example, it purifies the chromium by opiography in II min, the reference time 5.80 - Acci - Phe-gg-Tyr (OMe) - D- Λ I aG I y - A rg - II c - Asp - A rg - II e -

Using Fmoe-Tyr (OMe) -OH and Fmoc-Aca-OH instead of Fmoc-βΛ I and -OII ti Fmoc-Ie e-OH instead of Fmoc-Me t-Oli and without Fmoc-Cha-OII, follow the procedure described in Example 1, a crude peptide is obtained which is purified by chromatography by chromatography under the conditions described (5% to 80% B in 1.1 min, retention time 6.85 min). FAB-MS (M + 11) + = 1376.2

Example 76

- Aca - Phe---rg - Phe-1) -A Ia-G I y -Arg -1) -I le-Asp-Arg-Ie e-

Using Fmoc-Aca-OH instead of Fmoc-β-Ia-OII and Fmoe-D-IIe-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, the crude peptide was obtained as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B at 11 in.in, retention time 7.10 min).

FAB-MS (M + H) &lt; + &gt; = 1346.0

Example 77

- - Aca-Phe-A-g-Phe-D-A-1a-Gly-A-g-Ie-D-Asp-Arg-Ile-____

Using Fmoc-D-Asp (tBu) instead of Fmoc-Asp (tBu) -OH, Fmoc-Aca-OII instead of Fmoc-βΑ I α-OII and I-'nioc-I le-OII instead of Fiiiiic-Met-OII and without Fmoc-Cha-OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in 1 min, retention).

6.60 m (n).

FAB-MS (M + H) &lt; + &gt; = 1345.0

Example 78

-Aca-Phe-D-Ar-Phe-D-Pha-Phy-Ar-1 le-Asp-Arg-Ie

Using Fmoc-D-Arg (M tr) -Oll and Fmoc-Aca-OII instead of Fmoc-βAa-OH and Fmoc-Ile-011 in place of Fmoc-Me-Oll and without Fmie-Cha-OII, follow the procedure as described in Example 1 yields the crude peptide which is purified by chromatography over the conditions described (5% to 80% B in 11 min, retention time 6.65 min). FAB-MS (M + H) &lt; + &gt; = 1346.0

Example 79

-Aca-D-Phe-Arg-Phe-D-Ia-Gly-Arg-Ile-Asp-Arg-Ie-

Using Fmoc-D-Phe-OH and Fmoc-Aca-OH instead of Fmoc-pAIa-OH or Fmoc-I le-OII instead of Fmoc-Me t-OII and without Fmoc-Gha-OII, crude was obtained as described in Example 1 peptide which is purified by chromatography on% B in 11 min, retention time FAB-MS (M + 11) + - 1346.0% (6.55 min).

conditions (5% per «SO

Example 80

-Phe-Arg-Phe-D-Λ 1a-Gly-A-g-Ie-Asp-A-g-Ie

Using Fmoe-Ie e-011 instead of Fmoe-Met-OII and without Fmoe-Cha-OH and Fmoe-Aea-OII, the crude peptide was purified as described in Example 1 and purified by ehromaography under the conditions described (5% to 80%). % B in 11 min, retention time

6.55 min).

FAB-MS (M + 11) + = 1232.5

Example 81

- -Λ I a - Phe - A rg - Phe - D - Λ I a - G I y - A rg - I c - Asp - D - A rg - I I e—

Using Fmoe-D-Arg (M tr) -011 and Fmoe-Ile-OH instead of Fmoe-Met-OII and without Fmoe-Cha-OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described ( 5% to 80% B per second, retention time

6.15 min).

FAB-MS (M + H) &lt; + &gt; = 1303.7

Example 82

- β-α-Plie - D-A-g-Phe - D-a-a-G-y-A-g-Ile-Asp-D-Arg-Ile-

i.

Using Fmoe-DA rg (M tr) -011 and Fmoe-I le-OH instead of Fmoc-Met-OII and without Fmoe-Cha-OH, the crude peptide was purified according to the procedure described in Example 1 and purified by fluorine togalal. under the conditions described (5% to 80% B in 1 min, retention time, 0.5 min).

FAB-MS (M + 11) + = 1346.0

Example 83

-Arg-Phe-D-Ia-Gly-Arg-Ie-Asp-Arg-Ie-

Using Fmoc-lle-OII instead of Fmoc-Met-OII and without Finoc-C'ha-OII and Fmoe-β-I a-OII, the crude peptide was purified as described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in 1 min, retention time

5.45 m in).

FAB-MS (M + 11) + = 1085.5

Example 84

-β-AI-Phe-D-Arg-Phe-D-Ia-Gly-Ig-Ie-Asp-Ag-Ie

Using Fmoe-I) -Arg (M t: r) -OH instead of Fmoe-g rg (M tr) -OH and Fmoe-I le-OH instead of Fmoc-Met-OII and run Fmoe-Cha-OII with the procedure as described in Example 1 yields a crude peptide which is purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.40 min).

FAB-MS (M + H) &lt; + &gt; = 1303.7

Example X5

- [beta] - [alpha] -Phe-Arg-Cha-Az t-Gly-Arg-11 le-Asp-Arg-11e -

Using Fmoc-Azt-OH instead of Fmoc-DA I a-OII and Fmoe-Ile-OII instead of Fmoe-Me t-011, the crude peptide was obtained as described in Example 1, which was purified by chromatography under the conditions described ( 5% to X0% B in 10 min, retention time 7.20 m in).

FAB-MS (M + 10 &lt; + &gt; = 1321.7)

Example X6

- -βΑ I α-Arg-I-D-a I α-G 1 γ-Arg-I e-Asp-Arg - I e e -

Using Fmoc-III c-011 instead of Fmoc-Met-011, the crude peptide was purified according to the procedure described in Example 1, and purified by fluorophilia from the described soils (5% to X0% B in 10 min, retention time 6.35 min).

FAB-MS (M + H) &lt; + &gt; = 1162.5

Example X7

Arg-Cha-D-Al-Gly-Arg-Ie-Asp-Arg-Ie-‘;

Using Fmoe-Ile-OH instead of Fmoe-Me t-011 and without

Fmoc-β-α-011 was prepared as described in Example 1 to give the crude peptide which was purified by chromatography under conditions described (5% to X0% B in 10 min, retention time 6.10 min).

FAB-MS (M + H) &lt; + &gt; = 1091.5 &lt; -1 &gt;.

í y i

Example 8-Phe-Arg-Cha-D-Al-Gly-Arg-Ile-Asp-Arg-11e

Using Li Ie-1-le-OII instead of Fmoe-Me L-Oll and without Fmoc-βα-α-OII, a crude peptide was obtained by the procedure described in Example 1, which was purified by digestion under the conditions described. (5% to 80% B in 10 min, retention time 8.25 min).

FAB-MS (M + 11) + = 1238.8

Example 89

II-Lys-A-g-Phe-Ι) -Λ I a-G-y-l-y-N-e-Asp-A-g-I e -

The peptide synthesis was performed on an Advanced ChemTeeh ACT 200 peptide synthesizer using Fmoc-s trategi e using a modified control program in a 50 ml shaker reactor. 1 g of 2-methoxyhexyl ester resins from Baclien, Switzerland were placed. The thorium was fed to a cycle of 0.5 mmol of Fmol-1 euine. The following amino acid derivatives were used: momoe-A ľg (M tr) -ΟΙ I, Fmoc-Asp (t Bu)-, I, Fmoe-NIe-OH, Fmoe-Lys (BOC) -O11, Fmoe-G γ- OII, Imoe-DA I and -OII, Fmoc-Phe-OH and BOC-Lys (Fmoe) -OH. The couplings were carried out using 3 equivalents each of Fm-amino acid, 1-hydroxybenzotriazole and other alkali metal (coupler time 40 minutes). After the TNBS test was performed, the incomplete aberration or dome of the cheek was repeated using the same reagents and excess. When complete, the next synthesis cycle is started. The cleavage of the Fmoc-amino and eh groups is performed with 20% piperidinoin in DMF (once 3 minutes, once 15 minutes).

Between individual reactions, the resin was p-washed 10 times with DMF. After construction of the I sequence sequence BOC-Lys-Arg (M tr) -Phe-D-Ala-Gly-Lys (BOC) -NI e-As p (t Bu) -Arg (M tr) -II e- on the polymer support, the resin is washed thoroughly with dichloromethane and then treated 5 times with 20 ml of a 1% solution of trifluoroacetic acid in dichloromethane at room temperature for a maximum of 10 minutes (until the resin is intensely colored) . The combined solutions are concentrated and concentrated in vacuo. The residue is triturated with ether, the ether is decanted off, the peptide is dried under a stream of nitrogen and taken up in 130 ml of DMF, the pH is adjusted to about 8.5 with triethylamine, the solution is cooled to -20 DEG C. and 0.2 g is added. (0.75 mmol) diphenyl I phosphorus azide. Neehii stood for 48 hours at. -20 ° C and 48 hours at 4 ° C. The pH is maintained at 8.5 with thylanine at 8.5. It is then removed in vacuo, the residue is triturated twice with ether, the ether is decanted off and the residue is dried. in a stream of nitrogen. The side chain protecting groups are cleaved with a mixture of trifluoroacetic acid / i (90/10) for 24 hours at room temperature. The solution was concentrated in vacuo, the residue was triturated with ether and dried. The crude peptide is purified through a 3 µm Dynamax 08 column (10 x 2.14 cm) using one of the A: water / acetonitrile / acidic gradients 95/5/0, 2 and B: dt to 20/80 / 0.2 from 5% B rm 80% B in 11 min, flow 20 ml, retention time 5.25 min. After freeze-drying, an amorphous colorless powder is obtained.

FAB-MS (M + H) &lt; + &gt; - 1186.0

Example 90

Z-Lys-Arg-Phe-DA I aG ly-Lys-N I-Asp-Arg-II Using Z-Lys (Fmoc) -OH, substitute BOC-Lys (Fmoc) -011 for the procedure described in Example 1 yields the crude peptide which is purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.60 miri).

FAB-MS (M + H) &lt; + &gt; = 1320.0

Example 91

Z- Lys-grg-Ser (Bz I) - Ι) -Λ I a-G γ-Lys - N Ie - Asp-A rg - I ee -

Using Z-Lys (Fiiioc) -ΟΙ I instead of BOL-Lys (1'-moc) -OH in Fmoc-Ser (Bz1) -OH instead of Fmoe-Phe-011, the crude peptide was obtained as described in Example 1, which was Purified by chromatography under the conditions described (5% to 90% B in 1 min, retention time 6.95 min).

FAB-MS (M + H) &lt; + &gt; = 1350.0

Example 92

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

Using Bz-Lys (Fmoe) -OH instead of BOC-Lys (Fmoe) -OH, the crude peptide was purified by the procedure described in Example I and purified by fluorination under the conditions described (5%). to 80% B in 11 min, retention time 6.00 min).

FAB-MS (M + 11) + = 1290.0

Example 93

Z-Lys-Arg-Phe-D-Ia-Gly-Arg-Ie-Asp-Arg-Ie -

Using Z-Lys (Fmoe) -OH instead of BOC-Lys (Fmoc) -011 and pretty Fmoe-NIe-OH and Fiiioc-Lys (ROC) -011, a crude peptide was obtained as described in Example 1, which was purified by eh ronia tog by refining the conditions described (5% to 80% B in II min, retention time 6.65 min). FAB-MS (M + H) &lt; + &gt; = 1348.0

Example 94

H-Lys-Arg-Cha-D-11a-Gly-Arg-Ie-Asp-Arg-Ie

Using Fmoc-Cha-OH instead of Fmoc-Phe-OII and Fmoc-II.e-OH instead of Fmoc-N1 e-OII and without Fmoc-Lys (BOC) -011, the crude peptide was obtained as described in Example 1, which Purify by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.00 min).

FAB-MS (M + 11) + = 1219.7

Example 95

Z-Lys-Arg-Cha-D-A1a-Gly-Arg-Ile-Asp-Arg-Ile-

Using Z-Lys (Fmoc) -011 in place of BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH in place of Fmoe-Phe-OII and 1'moe-I le-011 instead of Fmoe-Nl.e-011 and without Fmoc-Lys (BOC) -OH was prepared as described in Example 1 to give the crude peptide, which was purified by chromatography under the conditions described (5% nti 80% B in 11 min, retention time 6.35 min).

FAB-MS (M + H) &lt; + &gt; = 1353.7

Example 96

Menoe-Lys-Arg-Phe-D-Ia-Gly-Arg-Ile-Asp-Arg-Ie e—

Where to use Menoe-Lys (lmoc) -011 instead of BOC-Lys (Fmoc) -OH tt i

and Fmoe-I le-OII instead of Fmoe-N I e-011 and without. Fmoe-l.ys (BOC) -011 gave the crude peptide as described in Example 1, which was purified by roma to the described conditions (5% to 80% B in 11 mi π, retention time 8). 20 min).

FAB-MS (M + H) &lt; + &gt; = 1395.8

Example 97

Menoc-Lys-A-g-Cha-D-Ia-G-y-A-g-Ie-Asp-F-1-e

Using Menoc-Lys (Fmoe) -011 instead of BOC-Lys (Fmoe) -OH, Fmoc-Cha-OH instead of Fmoe-Phe-OH instead of Fmoe-Ile-OII instead of Fmoe-N! e-ΟΗ and without Fmoe-Lys (BOC) -011, the crude peptide was purified by the procedure described in Example 1 and purified by chromatography (20% to 80% B in II min, retention time 7.00). min).

FAB-MS (M + 11) + = 1402.0

Example 98

II - Lys - Lys - Cha - D - Λ I a - G I y - Λ r g - I I e - As p - A rg - 1 I e—

Using Fmoe-I le-OII instead of Fmoc-N 1 e-OII and Fmoc-Cha-OH instead of Fmoe-Phe-ΟΠ, the crude peptide was obtained as described in Example 1, which was purified by chromatography by the conditions described (5). % to 80% B in 11 min, retention time 6.40 min).

FAB-MS (M + H) &lt; + &gt; = 1191.8

Example 99

Z-Lys-Lys-Cha-D-Ia-Gly-Arg-Ie-Asp-Arg-Ie

Using Z-Lys (Fmoe) -OH instead of BOC-Lys (lmoe) -11 and Fmoc-Ile-OH instead of lmoe-NI e-OII, a crude peptide was obtained as described in Example 1, which was purified by chromatography from the conditions described above (5% to 80% B in 11 min, retention time 7.75 min).

FAB-MS (M + H) &lt; + &gt; = 1326.0

Example 100

Z-Lys-Phe-Phe-D-Ia-Gly-Arg-Ie-Asp-Arg-Ic

Using Z-Lys (Fiiioc) -OH instead of BOC-Lys (Fmoe) -011 and Fmoe-I le-011 instead of Fmoc-N le-011 the crude peptide was obtained as described in Example 1 and purified by ehromatography as described above. conditions (5% to 80% B in II min, retention time 8.40 mih).

FAB-MS (M + 11) + = 1339.0

EXAMPLE 101 (4-N0 ₂₎ Z-Lys-A rg-D-Cha-Λ I a-yA GI RG-I le-Asp-Arg-I I e

Using (4-NO ₂ ) Z-Lys (Fmoe) -011 instead of BOC-Lys (Fmoc) -OH, Fmoe-11 e-OH instead of Fmoc-N I e-Oil ti Fmoc-Cha-OH instead of Fmoc-Phe After the procedure described in Example 1, a crude peptide was obtained which was purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 8.45 min). FAB-MS (M + H) &lt; + &gt; = 1398.9

Example 102

Z-Lys-Orn-Cha-D-Al-Gly-Ir-Asp-Arg-Arg

-No-OH and Example 1

Using Z-Lys (Fmoe) -011 instead of HOC-Lys (Fmoe) -011, Fmoc-Cha-OH instead of lmoe-Phe-OII and Fmoe-Ic-011 instead of Fmocnav and Fiuoc-Orn (BOC) -011 was obtained by the procedure described in the crude peptide, which was purified by chromalography under the conditions described (5% to 80% B in 11 min, retention time 7.80 min).

FAB-MS (M + H) &lt; + &gt; = 1311.8

Example 103

H-Lys-Arg-Se (Bz1) -D-Ala-Gly-Lys-N-e-Asp-f-l-e

Using Fmoe-Se r (Bz I) -OH instead of Fmoe-Phe-011, the crude peptide was purified as described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in 11 in in, retention time 5). , 55 min).

FAB-MS (M + H) &lt; + &gt; = 1216.0

Example 104

Bz-Lys tArg-Phe-D-Ia-Gly-Lys-Nle-Asp-A-g-Ile -

Using Bz-Lys (Fmoe) -011 instead of BOC-Lys (Fmoe) -OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in 11 min). , retention time 6.40 min).

FAB-MS (M + H) &lt; + &gt; = 1290.0

Example 106

Bz - Ly s - A rg - Se r - (Bz I) -1) -Ala-Gly-Lys -NI e-Asp-A rg-I e -

Using three Bz-Lys (Fmoe) -011 instead of BOC-Lys (Fmoe) -011 and Fmoe-Ser (BzI) -OH instead of Fmoe-Phe, the crude peptide is purified as described in Example 1 and purified. by chromatography as described (5% to 80% B in 1 min, retention time 6.35 min).

FAB-MS (M + H) &lt; + &gt; = 1319.7

Example 107

Tos-Lys-Arg-Phe-D-A.IIa-Gly-Arg-Ile-Asp-Arg-Ie-

Using Tos-Lys (Fmoe) -OH instead of BOC-Lys (lmoe) -OH and Fmoe-I.1le-OII instead of Fmoe-N I e-OII, the crude peptide was obtained as described in Example 1, which Purify by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.90 min).

FAB-MS (M + H) &lt; + &gt; = 1367.7

Example 108

II-Lys-Arg-Phe-Cg-Arg-Ile-Asp-Arg-Ie-

Using Fmoc-Clg-OII instead of Fmoc-Gly-OH and instead of Fmoe-DA I a-OII and Fmoe-I le-OII, instead of Fmoe-N I e-OII, the crude peptide was obtained according to the procedure described in Example 1. Purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 4.85 min).

FAB-MS (M + H) &lt; + &gt; = 1253.8

Example 109

Z-Lys-A g-Phe-Cg-A g-I g-Asp-A g-Ile

Using Z-Lys- (Fmoe) -OH instead of BOC-Lys (Fmoc) -OII, Fmoc-Clg-OH instead of Fmoe-Gly-OH and Fmoc-I) -AI α-OII and Fmoc-I le-0H instead of Fmoc-NIe-OII ti without Fmoc-Lys (BOC) -OH, following the procedure described in Example 1, a crude peptide is obtained which is purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6). , 85 min).

FAB-MS (M + H) &lt; + &gt; = 1387.8

Example 110

Z-Lys-A rg-Cha-Cg-Arg-Ie-Asp-A rg-Ie

Using Z-Lys (Fmoe) -OH instead of BOC-Lys (Fmoc) -OH, Fmoe-Cha-OH instead of Fmoc-Phe-OII and Fmoe-1 le-OII instead of Fmoe-Nle-OII ti Fmoe-Cg- OII instead of Fmoe-Gly-OII ti instead of lmoe-DA.la-Oll1 without Fmoe-Lys (BOC) -OH as described in Example 1 gave crude peptide which was purified by chromatography under the conditions described (5%). to 80% B in 11 min, retention time 8.70 min).

FAB-MS (M + 1) + = 13 94.0

Example 111

Z-Lys-Arg-Cha-D-CIg-Arg-Ie-Asp-Arg-Ie-

Using Z-Lys (Fmoe) -OH instead of BOC-Lys (Fmoe) -Ol1. Finoc-Cha-OH instead of Fmoe-Phe-OII, Fmoe-Cg-011 instead of Fmoe-Gly-OII and Finoe-D-AI a-OII and Fmoe-I le-OII instead of Fmoc-NIe-OII and

00 without Fmoc-Lys (BOC) -OH followed by the procedure described in Example I gave the crude peptide, which was purified by chromatography under the conditions described (5% to 80% B in 10 min, retention time 9.80 min). FAB-MS (M + 11) + = 1393.9

Example 112

H-Dap-A rg-Cha-D-A.l a-G-y-fg-I e-Asp-A rg-I I e-

Using BOC-Dap (Fmoe) -011 instead of BOC-Lys (Fmoe) -OH and Fmoc-Ile-OH instead of Fmoe-NIe-OH and without Fmoe-Lys (BOC) -011 was obtained as described in Example 1 to obtain the crude peptide which was purified by chromatography using the conditions described (5% to 80% B in 10 min, retention time 6.85 min).

FAB-MS (M + H) &lt; + &gt; = 1177.5

Example 113

Z-Dap-A-g-Cha-D-A-a-G-y-A-g-J-e-Asp-A-g-I-e

Using Z-Dap (Fmoc) -OH instead of BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH instead of Fmoe-Phe-OII and Fmoe-I I c-011 instead of Fmoe-Nle-OH and without Fmoc-Lys (BOC) -OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B in 10 min, retention time 8.10 min).

FAB-MS (M + H) &lt; + &gt; = 1311.6

Analogously, the right Lavi (4-N0 ₂₎ Z-Lys-Arg-Cha-DA 1-yl GI-Arg-Me t-Asp-Arg-I I e

Purify by chromatography using the conditions described (10% to 90% B in 10 min, retention time 7.4 min).

FAB-MS (M + H) + = 1417.0 (4-N0 ₂₎ Z-Lys-Orn-Cha-DA 1-G1y-Arg-I-1 E-Asp-I and R 1 e

Purify by chromatography under the conditions described (10% to 90% B in 10 min, retention time 7.8 min).

FAB-MS (M + 10 &lt; + &gt; = 1356.6)

Example 114

2-Pyridylation-Lys-Arg-Cha-P-A1a-Gly-fluor-1e-Asp-Arg-Ic

Peptide synthesis is performed on an Advanced ChemTech ACT 200 peptide synthesizer using Fmoc-s trategi e using a modified control program in a 50 ml thaw reactor to place 1 g of 2-methoxyhenzyl ester resin from Bachen, Switzerland, which was charged to a cycle of 0.5 mmol. Fmoc-i from eucine. The following amino acid derivatives were used: Finoc-Arg (M tr) -OH, Fmoc-Asp (tBu) -OH, Fmoc-11le-OH, Fnioc-Gly-011, Fmoc-DA 1 α-OII, Fmoe-Cha- OII and 2-pyridylation-tyl-Lys (Fmoc) -OH. The couplings were carried out using 3 equivalents each of F-amino amino acid, 1-hydroxybenzotriazole and dicalohexylcarboxylic acid (coupling time 40 minutes). After

I

The TNBS test was repeated in the case of incomplete coupling and repeated using the same reagents and excess. When complete, the larger synthesis cycle is started. The cleavage of the Fmoe-protecting groups is carried out with 20% piperidine in DMF (once 3 minutes, once 15 minutes).

Between each reaction, the resin was washed with DMF 10 times. After the construction of the linear sequence of 2-pyritlylacetyl-Lys-Arg (M tr) -Cha-D-Ia-Gly-Arg (M tr) -IIe-Asp (tBu) -Arg (M tr) -IIe na The resin is thoroughly washed with dichloromethane and then treated 5 times with 20 ml of three fluoroacetate in methylene chloride for a maximum of 10 minutes (until the resin is intensely colored). The solutions are purified and evaporated in vacuo. The residue is triturated with ether, the ether is separated off, the peptide is dried under a stream of nitrogen and taken up in 130 ml of DMF, the pH is adjusted to about 8.5 with triethylamine, the solution is cooled to -20 ° C and 0.2 g (0.75 mmol) of phosphoryl azide diphenyl 1 is added. Leave herds for 48 hours at. -20 ° C and 48 hours at 4 ° C. The pH value is maintained at 8.5 with amine. DMF was then removed in vacuo, the residue was triturated twice with ether, decanted off and dried under a stream of nitrogen. The side chain protecting groups and cleavages were cleaved with a mixture of L-trifluoroacetic acid / l (90/10) for 24 hours at room temperature. The solution is concentrated in vacuo, the residue is digested with ether and dried. The crude peptide was purified through a 3 µm Dynainax 018 column (10 x 2.14 cm) using one of the gradients A: water / acetonitrile / acid on trifluoroacetyl 95/5 / 0.2 and B: dtto 20/80 / 0.2 from 10% B to 90% B in 11 minutes, flow rate 10mL / min, retention time 8.2 minutes. After freeze-drying, an amorphous colorless powder is obtained.

FAB-MS (M + 11) + = 1338.6

Examples 115 to 124

X-Lys-Arg-Cha-D-Al-Gly-Arg-Ile-Asp-Arg-Ile

03

For λου-Lys (Fmoe) -OH, the pept.i.t is (10% to 90% table).

thia X-Lys (Fmoe) -011 instead of 2-pyridyl. The procedure was as described in Example 1 to obtain a crude purification of the crude oil under the conditions described B in 11 min. followed by í '. ·.', i '·.?

Pri k l.ad retention FAB-MS (M + 11) time (min)

9.5

9.9

8.7

1,338.6

1393, 7

1403, 6

1.3 2 5

1382, 8

1385,8 i

s

I ί

r i

l i

i.

i í

I!

and

I 04

Example #

120

121

122 ^{C 1} -O °

123

124

(1): Deviation from ie Valued time

7.6

8.1

7.5 cleaning according to example 1

B to 90% B in 10 m at flow I0 m I / m i n.

FAB-MS (M + II)

1415.7 (1417.7) 1 Br

1398.8

1388

1404

1422 »

I.

i í

05

Gel (for transdermal administration, in particular associated with it) of the active substance of the formula I in citrate buffer 4, 1 (composition see below)

0.25% agarose

Composition of citrate buffer pH 4.1

Solution I:

10.5 g of tin (III) citric acid morohydrate 100.0 ml of 1N sodium hydroxide to 500.0 ml of distilled water

Solution II:

100.0 ml of hydrochloric acid 0.1 mol / l to 250.0 ml of solution I

Higher said solution is heated about 60 ^(, C for mixing and after dissolution everything Time t The agarose is left vyehl adnú ť to room temperature. Solution for i n j eke i e 10,5 g Nall ₂ P0 ₄ .2H ₂ 0 95,5 g NaH ₂ P0 ₄ .12H ₂ O > P ti ľ e r pH 7.4 22,0 g NaCl up to 5000 iii.l distilled water

This buffer is treated in a lava flow for 30 minutes at. 121 ° C and 98.0665 kPa.

f ·. ·

· J ..

s

The

r. '.

i · '

06

To this solution is added 1.5 g of the formula (I) and the resulting solution is efficiently dried by filtration.

In the examples the compositions may be used as the compound of formula (4-N0 ₂₎ Z-Lys-Cha-rg Λ DA-I and G I yA RG-I I e-Asp, and R-I, I, E or other of the above of said compounds.

107

1> Λ T E N T 0

Claims (1)

1. Cy k 1 opepids of the general pattern I with ANI 'ugon with a low efficiency p- A n - B n - C n - D n - E n - i'n - Gn - II n - I n - K n-j (I) wherein the sequence of members Bn to Kn represents the sequence and inocyanate residues of h ANP -Arg (27) -Phe (B) -Gly (9) -Gly (10) -Arg (I1) -Me 1 (12) -Asp (I3) -Arg (14) I.le (15) - or its spatial structural and functional equivalents, and An is a spacer group that associates Bn with Kn and affects the spatial structure of these molecules by binding cyclopeptides to ANP receptors and even a pharmaceutically acceptable salt. The cyclic ophthalmology of claim 1, wherein the spacer group in the portion downstream of the member Bn comprises an aromatic or cyclic moiety and a heavy residue. Cyclopeptides according to claim 1 or 2, wherein the members Bn, Cn, En, Fn, Gn, Hn, I n or Kn are in L-form. T A cyclopeptide according to claims 1 to 3, wherein Bn is an α-amino acid residue with one or more side chains, wherein the side chain (s) or one of the two side chains comprises one, two, three or four basic groups. 10Κ Cn is an alpha-amine acid residue with one or two optionally -O-, -S- or -C (O) O- containing and I truss and side chains, wherein the side chain (s) bear (s). ) and one of which bears a radical or two radicals wherein each radical is cycloalkyl of 3 to 10 carbon atoms, phenyl, naľtyl, substituted for example by hydroxy, attributed to the (C j ₄₎ alkyloxy, (C j ₄₎ and Ikoxy, N0 _2, phenyl or a 5- or 6-membered aromatic heteroaryl wherein 2 members represent N or one N member and one is 0 or S or one member is N, S or O and the others are C, preferably thienyl, phenyl , pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl I, pirimidinyl 1, pyridazinyl I, indolyl, iinolyl, quinolyl, ch novels I, thiazolyl, oxazolyl, morphine I i ny I. Dn and En each independently of the other denoted by Gly or «- amino y is a new residue that mimics the spatial structure of the native amino acid Gly t or Dn and En together are 6d -AM and nokysel and new rest -Nll (CII ₉₎ | j -C0ale's peptide template, Fn is α-am.i nonacid. i a new residue with one or two side chains, wherein the side chain (s) t or one of the two side chains comprises one, two, three or four basic groups, Gn is a new residue with one or two lipids. The α-amino acid residue in the side chain (s) contains no functional group, or -COOII or -COOH ₂ contains as a functional group. In is an α-am amino acid and a new residue with one or two side Wherein the side chain (s) or one of the side chains comprises one, two, three or four basic groups, Kn is an α-amino acid residue with one or two 11pophilic side chains. A cyclic opeptide according to claim 4, kilo Bn, Fn, and In independently represent a side chain amino acid residue, wherein the side chain comprises one or two basic groups, Cn is an α-amino acid side chain residue, Dn and En are independently as defined in claim 4 or Dn and En together create au? -am i nokyse I i new rest -NH- (CII _{2) 2} _ j-CO- or a peptide Ľciiipláť. Gn and Kn are not independent of each other .alpha.-amine inyl acidic residue with an 11pophilic side chain, while the side chain is (C1-C6) alkyl, which may also contain one or two -S- or -G- in the chain, Hn is a Gly or α-am i.noacid residue whose side chain is (C1-C ₍ -) and I-I, phases I - (C1-C ₍ -) - and I-I, II ^ N) -CO- _(CH2) [_ ₄ or H00C- (CII _2), _ ₄ -, The cyclopeplid 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, preferably Arg, D-Arg, Lys, D-Lys or Orn, K) Cn means Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha, Ser (Bzl), D-Ser (Bzl), D-Ser (Bzl), Tyr, D-Tyr, Tyi (Bzl). (l) - l 'r (Bz I), Na I, D-Nal, Thi, I) - Thi, Asp (Bzl), D-Asp (hzl), His, D-llis, GI (Bz I) ) or DG.1.11 (Bzl), preferably Phe, Cha, Tyr, Na I, Tyr (Bzl) or (4-NO ₂ ) -Phe, Dn and En are each independently Ala, Gly, lin, Ser, Asn, Lys, Asp, or Thr or their D-forms, preferably 1) n, D-Ala. Gly, Pro, D-Pro, Ser, or D-Scr, En is Gly, Asp or Asn or Dn and En together are ω - i nokyse or I, and a new radical of formula --NH - (CII _{2) 2} _ I, -CO- or peptľídový template done without Btu, Clg, and the Tre eh or the D-form, in particular DB here, Cn and Kn are independently E1, D1e, Me, D-Met, Nle, D-NIc, Leu, D-Leu, Val or D-Vy1, preferably Ilc, Met, No or Leu; - (Cl ₁₂ ) ₁₄ -CII (NH -) - CO-, its D-forms, Gly, Ala, D-Ala, Asn, D-Asn, Phe or D-Phe, preferably Asp, Glu or Gly. A cyclopeptide according to any one of claims 1 to 6 kilo An je a) -A 1 -A 1 A 1 -, wherein A | is a Gly or an α-amine residue of an i-nynyl whose side chain (s) bear no functional groups, 1 I Znamená ₂ represents a metal bond or an α-amino acid residue of formula II wherein -NH- (CII ₂ ) _n -COn is a number from 1 to 11, (II) An is an alpha-amino acid residue with one or two optionally -O-, -S- or -C (O) O- containing alkyl side groups. wherein the side chain (s) or one of the two side chains bears one or two residues, each of said residues being in each case a cycloalkyl having from 3 to 3 carbon atoms. 10 carbon atoms, phenyl, naphthyl, and suhst monosubstituted with (e.g., hydroxy, fans 1 (C ₄ _) and l.ky.l.oxy, (C _ ₄₎ alkoxyl, N0 ₂₎ -phenyl or 5alebo 6-membered aromatic ical lieterocycle I, kile 2 ring members are N or one member is N and one is O or S, or one member is N, S or O, or the other members are C, preferably thienyl, phenyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidine d iny1, pyridazinyl, indolyl, isoquinilyl, quinolyl, ch novels I, thiazolyl, oxazolyl, morpholinyl, or b) -A ₄ -A ₄ -, wherein A ₄ denotes a thio-to-amine-cyanocyanate-I thietylacrylate residue NII- (CII ₂ ) _n -CO (II) wherein n is an integer from 1 to 11 I 2 signs! a covalent bond or an γ-amino acid residue with one or two optionally -O-, -S-, or -C (O) 0 containing both alkyl and side chains, wherein the side chain (s) or , one of the two side chains carries one or two radicals, each of which is a C 3 -C 10 cycloalkyl. The cabinet ubi, phenyl, naf'tyl group, a substituted (e.g., hydroxy, phenyl-I (C ₄ _) and I, I, alkyl oxy, (C j _ ₄₎ and l.koxy, N0 ₂₎ phenyl. or a 5-membered or 6-membered aromatic compound of formula 1, wherein the 2 ring members are N or one member is N and one is O or S, or one member is N, S or O, and the other members are C, preferably thienyl, fu ryl, pyrrol.y! , imidazoles 1, pyrazolyl, pyrimidinyl I, pyridazinyl, indolyl, pyrimidyl, pyrazinyl, isoquinolin-1-yl, chromanyl, thiazolyl, oxazolyl, morpholinyl or c) am i nokyseI and a new radical of formula III -NH- (CH _{2) and} CH (R) -CO- (III) wherein. m is an integer from 1 to 11 and R is NIIX, OX, SX, NXY, -Nll (II) -C (O) -Cll ₂ -X ¹ , -N (II) -C (O) -C 11 ₂ -OX ¹ , -N (II) -C (O) -X ¹ , -N (II) -C (0) -CH = ^CH-X1 or -N (II) -C (0) -O-C ¹ -X, wherein X is hydrogen, an unsubstituted or substituted radical benzoyIový, unsubstituted or substituted cyclohexylcarbonyl, unsubstituted or substituted benzyloxycarbonyl, 2-, 3-, or 4-pyridylmethoxycarbonyl or moiety, X is Cl is an O 4 -alkyl radical or an aryl- (C 1 -C 14 -alkyl) radical a I 3 X ¹ represents ()) women I, (β) 1, 2 or 3 substituents selected from the group consisting of halogen, trifluoromethyl I, or low-substituted phenyl, (R) naphthyl, (δ) benzo / b / thienyl I, ( 6) Pyrides I or (Ί) pyrazinyl. Cyclopeplid according to claim 7, wherein Λιι represents a) - A 1 - A ₂ - Λ 3 -, where A 1 represents a n-amino acid and a new radical with one (C 1-6) alkyl chain, A ₂ is a thiaminoacid I and a new radical of formula II wherein n is an integer from 1 to 6, Αβ is an α-am inocyanate residue or WITH one side a group -A ₄ A 4 - wherein A 1 is a radical u> of formula II, wherein n is an integer from 1 to 2; - tllll i 6 n 0 k y s e 1 i other ac; is both the α-amino acid and the new residue chain, with one side an amine acid residue of formula III, to those m is 1, 2, 3 or 4 and R is -NHX, -NHY, -NH (II) -C (O) -ΟΙ ₂ -Χ ', -N (II) -C (O) -Cl 2 -OX ¹ , -N (H) -C (O) -X ¹ - N (II) -C (O) - Cl 1 = CH-X ¹ or -N (II) -C (O) -O-CH ₂ -X ¹ . A compound according to claim 8, wherein An is (i) a group - A j - Λ ₂ - A ₃ - wherein A | means Ala, Gly, Phe, Val, Ile, Leu or No or their D-form, preferably Gly, Ala or D-Ala, A ₂ is o-amine with a new radical of formula II wherein n is 2, 3 or 5, I 1 4 A3 stands for Phe, D-Phe, , 4-NO ₂ Phe, Cha, l) -Cha, Se r (Bz 1), D-Ser (Bzl); , You, D-Tyr , Tyr (Bzl), D-Lyr (Bzl) Nal, D-Na 1, , T h i, D-Th i , Asp-Bzl, D-Asp-Bzl or II isa 1 e ho (4-NO ₇ ) Phe, D-11 is, 1 preferably Phe, Tyr, Cha, Na b) - A 4 - A 3 - group, k d e Λ4 is a radical of an amino acid of formula I, wherein n is 2, 3 and I or 5, 1'i · I: is Phe, D-Phe, l) -Sei (Bzl) , Tyr Nal, D-Na 1 , Thi II i s, D-11 i s , G 1 u Phe, Tyr, Cha, 4-NO ₉ -Phc, Cha, D-Cha, Ser (Bzl), D-Tyr, Tyr (Bzl), D-Tyr (Bzl), D-Thi, Asp (Bzl), I-Asp (Bzl) , (Bzl) or D-GI (BzI), preferably Nal or _(4-NO2) Phe, or c) an even acidic radical of formula III wherein m is 1, 2, 3 and because R is as defined in claim 8 wherein X is hydrogen, unsubstituted or chlorine, methoxy or (C1 to C3); and A 1-kyl-substituted benzoyl residue, a cyclooxyxy- or ( a methyloxycarbonyl residue, unsubstituted or methoxy, i nitro, trifluoromethyl I or a cyano-substituted benzyloxycarbonyl radical, preferably benzyloxycarbonyl I, e.g. 4-methoxybenzyl oxyka rbon 1, 2 or 4-trifluoromethyl ifluórmety IbenzyI - ί carbonyl, in particular benzyboxykarbonyI, 4 - trobenzy1oxykarbonyI add ¹ or 2 or 4-trifluoromethyl-Iuórmety IbenzyIoxykarbony I, _t Y represents a C1-C14-alkyl radical or a (C1-C14-alkyl) phenyl radical, preferably benzyl or phenylethyl, and j i I i 15 χϊ denotes phenyl or mono- or di-substituted phenyl, 2-pyridyl, 2-pyrazinyl, 3-benzo [d] thienyl or 2-naphthyl. 10. The cycle of opep td d according to claim 1 to 9, wherein An sign! -A 1 -A 1 -A 1 -A 1 -, kile Gly, ^A 2 J ^l Aca, βΛ1 a, Apen, Oh yeah, Gly a 1 e b <> z name w e n t n ú dl bond and ^A 3 J * ¹¹ Phe, Phe (4-NO ₂ ) Tyr or Ty r (Bzl) or An represents a group -Λ ^ -Λ ^ -, where A ₄ is βΑΙ.a, Aea, The, Aund, B here or DB here and A $ is a covalent bond, Phe, D-Phe, Phe (4-NO?), Tyr, Tyr (Bzl) or Cha or An is an amino acid residue of formula (I) -NH - (CII2) n, -CH (R) -CO-, wherein m is I or 4 and R is a group -NHX, where X is II, Z., Bz, Name, (4-No -?) Z or Tos- or A n is X -Lys-, k those X is one of the following groups - 116 - Ο 1 7 Bn is Arg, D-Arg, Lys, Orn, or Cl'1, Cn is Cha, Phe, Ser (Bzl), Tyr, Lyr (Bzl) or 'Lyl (Me), Dn is D-Ala, Pro or D-Pio, En is Gly, and I e bo Dn and En together form L-Clg, D-Clg or D-Btu, Fn is Arg or Lys, Gn is white, D-white, No or Met, Hn is Asp, D-Asp or Gly, In is Arg or D-Arg and Kn is clay. The cyclopeptide of claim 10, wherein An is -G I y-βΑ I and-Phe-, -G I γ-βΑI α-Tyr (BzI) -, -βΑI and-Phe, -βα la-Plie (4-NO ₂ ) -Lys- - (4-N0 ₂₎ Z-Lys, Lys Bn is Arg, Lys, Ctr or Orn, Cn is Cha or Phe, Dn is D-λ la. En is Gly, Fn is Arg, Gn is clay or Met, Hn is Asp, In is Arg and K n j e 1.1 e. A cyclopeptide according to claim 1 BA1a-Phe-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly pBAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg -Ιle-GlyR-Bala-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Phe _r, BAla-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp Arg-Iler-BAa α-Phe (4-NO 2) -Arg-Cha-D-Ala-Gly-Arg-11 le-Asp-Arg-Phle-BAl α-Phe-Ctr-Cha-D-Al and -Gly-Arg-Ile-Asp-Arg-1le ₃ (4 -NC> 2) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-IleX-Lys-Arg -Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ilede (4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-1e-. (4 -NC> ₂ ) Z-Lys-Orn-Cha-D-Al and Gly-Arg-Ile-Asp-Arg-1919 and its pharmaceutically acceptable salts 13. A method of making ey k I opep t: clays of any of the above. of claims 1 to 12 or salts thereof, characterized in that linear peptide sequences are generated from the corresponding fragments by known methods in peptide chemistry; then sa eyk l. and if it is to po t r easy to create the corresponding salts. 14. Fa rinaceu threefold content of 1-membered pod ľ Any of claims 1 to 12. 15 Dec Use from 1 efficacy according to n i e k torélio of the claims 1 to 12 for the production of antihypertensives knows (eventually hypotension í va. 16th Use of the compounds according to n i t: k torélio of the claims 1 to 12 for the manufacture of diuretics. 17th Use of the compound according to n i ek torélio of the claims 1 to 12 for the production of ligaments 18. It is also possible to use the compound according to any of the claims 1 to 12 to produce spasmo1. 19 Dec Use of the first compound according to n i ek torélio of the claims 1 to 12 for the production of the top.