PL168456B1 - Method of obtaining cyclopeptides - 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

The subject of the invention is a method of producing new cyclopeptides composed of natural and unnatural amino acid residues. Peptides are agonists of ANP.

The new cyclopeptides are partial sequences, sequences partially interconnected in a discontinuous manner, modified partial sequences, and analogs of the so-called atrial urinary sodium excretion factor, ANF, or 'atrial urinary sodium excretion peptide, ANP.

ANP is synthesized mainly in the muscle cells of the atria of the heart, there it is also stored as a prohormone and released as a result of a mechanical stimulus of increased wall tension. It relaxes the vessels, lowers blood pressure, has diuretic and saluretic properties, increases glomerular filtration, reduces plasma volume and increases hematocrit, lowers plasma renin activity and plasma aldosterone levels, has spasmolytic and broncholytic properties. This action is mediated through specific receptors.

The abbreviations used in this specification and claims are in accordance with the recommendations of the IUPAC-IUB Joint Commission of Biochemical Nomenclature / Eur. J. Biochem. 138, 9-37 (1984). Some other abbreviations have been supplemented. Some of these abbreviations are listed below:

Aund ω-aminoundecanoic acid Abut γ-imiinobutyric acid Aoc ω-aminoctaryqq.sq Apen δ-aminopenanoic acid Aca ε-aminocaproic kwss Aib acid c-ą ^ multiplication ^^ c ^ naiskw ^ p ' Ala alanñna chump β-alanine Arg argmma Asp aspa-aginic acid 0 Azt '1

168 456

Boom

BOC

Btu

Bzl

Bz

Cha

Cle

Clg

Ctr

Dap

DMF

DPPA

DCC

DIC

Gly

His

HOBt

How much

Leu

Lys

Menoc

Me

Underworld

Mtr

Nal

Nle

Orn

Phe

Pmc

Cheese

The

Tertiary butyloxymethyl

ΠI-née butioksykcrbonsi

3-amino-1-kcrboxymethyl-pyrrolidin-2-one benzyl benzole cyclohexylalanine cycloleucine

3- amino-1-carboxymethyl-hexahydiOazepin-2-one citralin 23-L “diaminopropionic acid

N, N-dimethylformamide diphenyl phosphoazide dίcycrohexyrocarbodiimide άϋζορΓορν ^ ϋΛ ^ ΐΐπύά giicin histine L-hydroxybenrotriarol isoleucine leucine gin mentyoxycarbonyl meyyl meiiomna

4-meroxy-2,3,6-arimeSyrsSenyrosuironyl

CH- © CH © --CHNW-COOH oπliSyna penyroaCanrna penCπmeSyrochromanosuirseyin

3cπmrno-7-carboxytletcahydroizochrnoirnl Thi

Tos

-CH ₂ -CH / NH ₂ / -C00H tosyl

Trt trityl

Tyr tyrosine

VA1 valine

From brln <y! Qkkykacboίry!

The phrase amino acids (unless expressly stated otherwise in the following text) includes natural and unnatural amino acids, both the D and L forms. In addition, the phrase α amino acids also includes α, α-disubstituted amino acids.

If the amino acid is given without the prefix / e.g. Orn /, this data concerns the L form of the amino acid. Form D is clearly given / e.g. D-Orn /.

The invention relates to cyclopeptides of the general formula I having agonistic activity

ANP r-An-Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn-, / 1 /

168,456 in which the sequence of Bn and Kn is the sequence of the hANP amino acid residues

-Arg / 27 / -Phe / 8 / -Gly / 9 / -Gly / 10 / -Arg / 11 /

Met / 12 / -Asp / 13 / -Arg / 14 / -Ile / 15 / - or their equivalents in terms of spatial and functional structure, and An is the spacer group that binds Bn with Kn and affects the spatial structure of the respective molecule yes, that cyclopeptides bind to ANP receptors, and their pharmaceutically acceptable salts.

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

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

The spacer An group holds the α-C-atoms of the Bn and Kn members 5 to 15 angstroms apart. (Conferences on 20-NMR measurement in aqueous solution, results as boundary conditions for molecular dynamics simulation).

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

By sterically equivalent and functional equivalents of ANP amino acid residues are meant the amino acid residues or peptide forms (both L and D forms) which cause the cyclopeptides of general formula I to bind to ANP receptors. Previous studies have shown that, for example, the sequence (Bn to Kn) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- shows very good receptor binding values and pharmacological activities.

The individual members of this order may be replaced with residues of similar spatial structure and / or function, with this having a greater or lesser impact on the receptor binding capacity and degree, and in some cases, the type of pharmacological action within the known ANP agonist activity is altered. Thus, by altering the individual members, the type, degree and duration of the pharmacological action can be influenced. When more than one term of Bn to Kn is changed, then according to the prior art the change in pharmacological properties consists of changes in the respective unit variations. The following compilation shows, on the basis of structurally similar examples, the relationship between the receptor binding capacity and the sequence of the members of the cyclopeptides of the general formula I.

(For a description of the tests see further in the text: Binding to ANP / receptors.

Compounds marked with x / exhibit IC 50 values in the aforementioned o-receptor binding assay

ANP less than 5.10 'mol, other compounds show lower affinity.

A1 a - p te e - A rr g - P le e -D- A1 a - G1 yA r g-Ile-Asp-Arg-Il t

D ^X /

Ala-Phe-Arg-Phe-D-A la-Gly-Arg-Ile-A sp-D-Arg-Ile-ł

Ala — P hA-P — itrg-PSe-P-IlastAly-Urp — ASg — P SA-P — Aip-1 leZ-Dap — Arg — Cha — D — Ala — Gly — Arg — Ile — Asp — Arg — Ile -i, x /, x /

168 456

H-Dap-Ar g-Cha-3-Ala-Gly-Arg-Ils-Asp-Arg-IleAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

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

I - Ala-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile-j, x / β Ala-Phe-Arg-Cha-D-Ala-Gly-Arg -Ile-Asp-Arg-II <

- Ala-Ar g-Cha-D-Ala-Gly-Arg-I le-Aso-Arg-Ile-j 'i

As already stated above, the expression amino acids includes natural and unnatural amino acids. Unnatural amino acids are preferred, unless further details are explicitly given, with respect to their molecular weight or side chain lengths, in the order of the size of the natural amino acids.

Suitable salts are, in particular, those with physiologically acceptable inorganic or organic acids, such as, for example, HCl, HBr, H2SO4, H3PO4, maleic acid, fumaric acid, citric acid, tartaric acid, acetic acid.

The chiral centers in the new peptides may each have the R, S or R, S configuration.

The terms Bn, Fn and In correspond to Arg / 27 /, Arg / 11 / or Arg / 14 / ANP or their spatial and functional equivalents. Bn, Fn and In may independently of each other be α-amino acid residues with two basic side chains or preferably with one basic side chain. By basic side chain is meant here preferably an alkyl or cycloalkyl side chain containing 1 to 4 (preferably 1 or 2) basic groups. Suitable basic groups are e.g. -NH-, = NH, -CH ₂ , -HN-C / NH / -NH ₂ , -C / NH / -NH ₂ . Preferably, at least one of the basic groups in each side chain is a difinite basic group. In addition, side chains in which the first basic group is attached to the δ-carbon of the α-amino acid or to a carbon atom which is still further away from the peptide backbone are preferred. Crude alkyl chains of 1-6, especially 3 or 4, carbon atoms and cycloalkyl side chains - / CH ₂ / _X - (CA) - / CH ₂ / _y - are preferred, in which x and y are independently 0, 1 or 2, and (CA) is cycloalkyl of 5 or 6 carbon atoms. Preferably, the basic group is at the end of the side chain.

The Cn term corresponds to Phe / 8 / ANP or its structural and functional equivalent as noted above. Cn may be an α-amino acid residue with two lipophilic side chains or preferably one lipophilic side chain. A lipophilic side chain at this position is taken to mean an alkyl side chain having 1 to 7 C atoms (preferably 1 to 4 C atoms, especially 1 C atoms). This alkyl side chain may contain one or two oxy (-O-), thio (-S-) groups or -C / O / O- groups. This alkyl side chain has one or two residues. These residuals independently of each other are residuals cvk1oaliphatic «· jj cu fa" t ~ ~ zl i ~ / U o -, -, roz 4 ~ ~ - ,, 1i1 ^ 11 g ~, ~ _Λ p .i O ujumui »« urnaiyv £ uyuu. ANk ^ Ld ν ^ Μυωιιαψυζ, πα giupaujMUaiMiuwa; ζ, α, d to 10, preferably 4 to 7, carbon atoms. The aromatic moiety is preferably a phenyl, naphthyl, substituted (e.g. by NO2, hydroxy, phenyl (C 1-4) alkyloxy or C 1-4 alkoxy) phenyl or 5- or 6-membered, optionally also benzene-fused, aromatic heterocyclic group in which 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl , chromanyl, thiazolyl, oxazolyl, morpholinyl.

The members Dn and En correspond, as stated, to Gly / 9 / or Gly / 10 / ANP or their spatially structural and functional equivalents.

Dn and En independently of each other can be Gly or an α-amino acid residue that maps the spatial structure of the natural amino acid / Gly /, or Dn and En together can be an ω-amino acid residue -NH / CH 2 / 2-11-CO- or the form peptide. At the Dn and En positions, preferably amino acid residues are suitable which, according to the statistical analyzes by Chou and Fasman (Biophysical Journal, Vol. 26, 1979, C67-C8C), are frequently in β-turn conformations. For example, amino acids that occur with increased frequency in positions i + 1 and i + 2 should be emphasized, especially those with a frequency of 0.06 (table 1 of the publication).

As suitable peptide forms, those having a β-turn mimicking conformation should be highlighted.

The terms Gn and Kn correspond, as mentioned above, to Met / 12 / or Ile / 15 / ANP or their spatially structural and functional equivalents. Gn and Kn independently of each other may be α-amino acid residues with two lipophilic side chains or preferably one lipophilic side chain. A lipophilic side chain at these positions is understood to mean preferably an alkyl side chain with 1 to 10 C atoms, preferably 1 to 6 C atoms, in particular with at least C atoms. This alkyl side chain may additionally contain 1 or 2 oxy / - groups. O- / or thio (-S-) (as for example in methionine). This side chain can also contain 1 to 2 alkyl groups.

The Hn term corresponds, as mentioned above, to Asp / 13 / ANP or its spatially structural and functional equivalents. This member acts as a space group. Hn may be an α-amino acid residue, namely a Gly, or a residue that does not contain an or -COOH and / or -CONH2 functional group in the side chain. Preferably the side chain is an alkyl side chain with 1 to 6 (preferably 1-C) carbon atoms, which may also contain a phenyl group and / or HOOC / CH2 / 1-4 or H2N-CO / CH2A-4-.

An is a spacer group as described above. This group may constitute

a) group -A1-A2-A3 b) group -A4-A5c) amino acid residue of formula III

-NlL / CHT / m-CH / Ry-CO- / III /

A1 may be a Gly or an α-amino acid residue with two side chains or preferably one side chain. These side chains do not contain any functional groups. Preferably such side chain is a branched or unbranched alkyl side chain with 1-6 carbon atoms.

A2 is a covalent bond or a ω-amino acid residue of formula II -NH- (CH2) - CO- / II where n is an integer from 1 to 11 (preferably 1 to 6)

A3 may be an α-amino acid residue with two lipophilic side chains or preferably one lipophilic side chain. A lipophilic side chain at this position is taken to mean an alkyl side chain having 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, especially 1 carbon atoms). This alkyl side chain may contain one or two oxy (-O-), thio (-S-) groups or -C / O / O- groups. This alkyl side chain has one or two residues. These residues are each independently cycloalkylphatic or

168,456 aromatic. A cycloaliphatic group (preferably a cycloalkyl group) contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic group is preferably a phenyl, naphthyl substituted (e.g. by NO 2, hydroxy, phenyl (C 1 -C 4 -alkyloxy or C 1-4 alkoxy) phenyl or a 5- or membered, optionally also benzene-fused, aromatic heterocyclic group in which 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidines! pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl.

A4 may be the peptidetemplat peptide form or the ω-amino acid residue of the formula -NH- (CH2 / n -CO- / II) where n is an integer i to ii (preferably i up to 6).

Included in the term peptide species are groups such as, for example, Clg, Btu, Thc and Trc. A5 can be a covalent bond or an α-amino acid group with two lipophilic side chains or preferably one lipophilic side chain. By lipophilic side chain at this position is meant an alkyl side chain of up to 7 C atoms (preferably up to 4 C atoms, in particular 0 and C atoms). This alkyl side chain may contain one or two oxy (-O-), thio (-S-) or -C / O / O- groups. This alkyl side chain has one or two residues. These residues are independently of each other cycloaliphatic or aromatic groups. A cycloaliphatic group (preferably a cycloalkyl group) contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic group is preferably a phenyl, naphthyl group, substituted (e.g. by NO 2, hydroxy, phenyl (C 1-4) alkyloxy or C 1 -C 4 alkoxy) phenyl or a 5- or 6-membered group, optionally also fused to a benzene ring, an aromatic heterocyclic group in which 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the remaining members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidines! pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl.

An can also be an amino acid residue of the formula III ^ - (0 ^ 2) ^ ^ / ^ - ^ (III) where m is an integer i to ii, and R is the group NHX, OX, SX, NXY, -NH / H / -C / O / -CH2-Xi,

-N / H / -C / O / -CH2-O-Xi

-n / h / -c / o / -x!

-N / H / -C / O / -CH = CH-Xi or

-N / H / - C / O / -O-CH2-Xi where

X represents a hydrogen atom, an unsubstituted or substituted benzoyl group, an unsubstituted or substituted cyclohexyloxycarbonyl group, an unsubstituted or substituted benzyloxycarbonyl group, a 2-, 3- or 4-pyridylmethyloxycarbonyl group, or a tosyl group,

Y is Cudo CH-alkyl or coarsely - / <H 1 to C1Zsalkyl

Xi stands for / α / phenyl, / β / by i, 2 or 3 substituents (halogen, trifludromatyl or nitro substituents), substituted phenyl, / γ / naphthyl, / δ / benpo [b] thianyl, / ε / pyridyl or / η / pyrazinyl.

The amino acid residue of formula III is preferred, where m is i, 2, 3, or 4 and R is -NHX, -NXY,

-NH / H / -C / O / -CH2-X1

-N / H / -C / O / -CH2-O-Xi

-N / H / -C / O / -X \

-N / H / -C / O / -CH = CH-Xi or

-N / H / -C / O / -O-CH2-Xi

Preferred cyclopaptics of the general formula are those in which: Bn, Fn and In are each independently Arg, D-Arg, Lys, D-Lys, Orn, D-Orn, homo-Arg, D-homo-Arg, Dap, D-Dap or 4-amind-Pha, preferably Arg, D-Arg, Lys, D-Lys or Orn;

168 456

Cn is Phe, D-Phe, 4-NO2-Phe, Cha, D-Cha, Ser / Bzl /, D-Ser / Bzl /, Tyr, D-Tyr Tyr / Bzl /, D-Tyr / Bzl /, Nal , D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or D-Glu (Bzl), preferably Phe, Cha, Tyr, Nal, Tyr (Bzl) or (4-NO2) -Phs;

Pin 1 Prn rno τ '^ 11 1 JL— / L1

Δία Λν1ν Pm Qp> r, ηνι.? Ιν Jiunv r »14 i nu.) Ν · *» jjx iw, _f

Δ cr »T vc Δ cn lnh Tbr inb

X mU) X xr X ill I-i-iuc AVH of form D, preferably Dn is D-Ala, Gly, Pro, D-Pro, Ser or D-Ser;

En is Gly, Asp or Asn; or

Dn and En together are an ω-amino acid residue of formula -NH- / CH2 / 2-5-CO- or a peptide form, preferably Btu, Clg, The or Trc or their D-forms, especially D-Btu;

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

Hn is HOOC- (CH2) 1-4-CH - / - CO-, their D, Gly, Ala, D-Ala, Asn, D-Asn, Phe or D-Phe forms, preferably Asp, Glu or Gly;

An a / An is the group - Ai - A2 - A3 - in which

Ai is Ala, Gly, Phe, Val, Ile, Leu or Nle or a D-form thereof, preferably Gly, Ala or D-Ala; '

A2 is a ω-amino acid residue of formula II, wherein n is 2, 3 or 5;

A3 stands for Phe, D-Phe, 4-NO2-Phe, Cha, D-Cha, Ser / Bzl /, D-Ser / Bzl /, Tyr, D-Tyr, Tyr / Bzl /, D-Tyr / Bzl /, Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His or D-His, preferably Ps, Tyr, Cha, Nal or (4-NO2) Phe; or

b) the group - A4 - A 5 - in which A4 is a ω-amino acid residue of formula II in which n is 2, 3 or 5;

A5 stands for Phe, D-Phs, 4-NO2Phs, Cha, D-Cha, Ser / Bzl /, D-Ser / Bzl /, Tyr, D-Tyr, Tyr / Bzl /, D-Tyr / Bzl /, Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or D-Glu (Bzl), preferably Phe, Tyr Cha, Nal or (4) -NO? / - Phe; or

c) an amino acid group of formula III where m is 1,2,3 kfo4 cR.rpnccec-NHX or -NXY, where X is hydrogen, unsubstituted with either chlorine, methoxy or (C1 to C3) alkyl substituted with benzoyl, a cyclohexyloxy or menthyloxycarbonyl group, unsubstituted either by a methoxy, nitro, thaiSluoomstyl or cyano substituted benzyloxycarbonyl group, preferably a benzsloxcarbonyl group, 4-methoxybsnzyloxycarbonyl, 2 or 4-taifluoromoxycarbonyl group, especially 4-taifluoromoxycarbonylobenzyl, especially 4-taifluoromoxycarbonylobenzyl 4-triSluoaomethylbenzyloxskaabonyl,

Y is a C1 to C14 alk11 or a (Cl to C14 alkyl) tense, preferably benzyl or phenylethyl; and X1 represents a phenyl group or a mono- or disubstituted phenyl group, 2-diridyl, 2-pyraesnylbw, 3-beneb [b] thienylbw or 2-naphthyl, especially those in which

An denotes the group - A1 -A2 -A3 in which

A1 stands for Gly,

A2 is Aca, pAla, Apen, Abut, Gly, or a covalent bond, and

A3 is Phe, Phs (4-NO2), Tyr or Tyr (Bzl); or

An denotes the group -A4 - A5 where A4 benacea pAla, Aca, Thc, Aund, Btu or D-Btu, and A5 benαcec covalent bond, Phs, D-Phe, Phe (4-NO2 /, Tyr, Tyr / Bzl / or Cha; or

An denotes an amino acid residue of formula III

-NH- / kH2 / r-kH / R / -CO where m is 1 or 4 and R is the group -NHX where X is H, Z, Bz, Menoc, M-NO2 / Z, Tos, or An is χ2 - Lys -, where χ2 is jsd of the following groups

9r

168 456

There are cyclopeptides of the general formula Ia pA ^ -A2-A3-B ⁿ -Cn-D ⁿ -E ⁿ -F ⁿ -Gn-Hn-In-Kn and their salts, where A? stands for Aund,

Aca, β-Ala,

Apen,

Abut either

Gly or a covalent bond;

A3 is Phe,

Phe / 4-NO ₂ /,

Ha,

Tyr or Tyr / Bzl /;

Bn is Arg;

Cn stands for Phe,

Ha,

Tyr, or Tyr / Bzl /;

Dn stands for D-Ala,

168 456

Pro or D-Pro;

En is Gly; or

Fin and Fn rn7Pm rGmcwaziz β-Ala,

Abut,

Aoc,

L-Clg,

L-Btu or D-Btu;

Fn is Arg or Lys;

Gn means Ile,

Underworld

Aib or Nle;

Hn is Asp or Aib;

In is Arg;

Kn means Ile and a

Ai means Gly.

Particularly preferred are cyclopeptides or their salts, in which A2 is a ω-aminoalkanoic acid residue of the formula -NH- / CH2 / 2-4-CO-;

A3 is Phe, Tyr, Cha, Nal or 4-NO2-Phe;

Bn, Fn and In are each independently Arg, D-Arg, Lys, D-Lys, Orn or Ctr; Cn is Phe, Cha, Tyr, Nal or Tyr (Bzl);

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

En is Gly or Ala; or

Dn and En together are D-Btu;

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

Hn is Asp, Glu or Gly; and Ai is Gly, Ala or D-Ala; especially those in which

A2 is β-Ala,

Apen or Abut;

A3 is Phe,

Phe / 4-NO2 /,

Cha or Tyr;

Bn is Arg;

Cn stands for Phe,

Ha,

Tyr or Tyr / Bzl /;

Dn is D-Ala;

En is Gly; or

Dn and En together are D-Btu;

Fn is Arg or Lys;

Gn means Ile,

Met either

168 456

Nle;

Hn is Asp;

In is Arg;

Kn means Ile and a

Ai means Gly.

Particularly preferred compounds according to the invention are:

1. i-Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly2. | -fica-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-ArG-Ile-Gly- | . -Aca-Phe-Arg-Phe-D-Ala-Gly-Ly s-I le -.-. sp-Arg-Ile-Gly- |

4.- (2> la-phh - Ag-phh ---- Bt - Ag - Il - Ss - Ag - ll-GGy5. - βAla-Phe-AAg-Phe-D-Ala -G ^ ly ^^ i ^ i ^ c ^^ ULa ^ / Ssf ^^ i ^ igg ^ ll-Gly6.f-Phs- / 4-NG2 / -Arg-Phe-D-Ala-Gly-Arg-Ils -Asp-Arg-Ile-Gly. Pe? Ala-Phe-AAg-Phe-D-Ala-Gly-AAg-r, et-A ss-Arg-Ile-Gly} Ala-Cha-Arg-Cha-D- Ala-Gly-Arg-Ile-Ass-Arg-Ile-Gly

- p Ale-Phe / A-NGg / -Arg-Phe-D-Ala-Gly-AAg-Ils-Ass-AAg-Ile-Gly-β Ala- Phl / 4-NC2 / -AAg-Cha-D- AIa-Gly-AAg-Ile-Ass-AΓg-Ile-Gly

Ala-TyA-Arg-Cha-D-Ala-Gly-Arg-Ils-A ss-Arg-Ile-Gly

Ala-Tyr / Bzl / -Arg-Cha-D-Ala-Gly-Arg-Ile-Ass-Arg-Ile-Gly

168 456 —Aca-Phe-Arg-Pheβ ^Α la-Arg-Ile-Aso-Arg-Ile-Gly

-

ca-Phe-Arg-Phe-Abut-Arg-Ile-AsD-Arg-Ile-Gly — Apen-Phe-Arg-Phe-D-Ala-Gly-Arg-Ils-Asp-Arg-Ila — Gly-n

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

j-Gly-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-GlyAla-Arg-Phe-D — Ala — Gly — Arg — Ile — Asp — Arg — Ile — Gly—

-Aca-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-, —Aund — Arg — Phe — DTAla - GlyTArg — Ile — Asp-Arg-Ile-Gly-j —A , ca — Phe — Arg — Phe — Aoc-Arg — IlB — Asp — Arg — Ile-Gly— β p Ala-Phe-Arg-Phe-Dila — Gly — Arg — Aib — Asp — Arg — Ile — Gly p

- β AlaTPhs-Arg-Phe-D-AlaTGly-Arg-Ile-Aib-ArgTIleTGlyT - β AlaTPhe-Arg-Phe-LTBtu-Arg-Ile-AspTArg-Ile-GlyŁL _____ I

- β Ala-Phe-Arg-Phe-DTBtuTArgTileTAsp-ArgTIleTGlyT

Ll______________ .. I

AlaTPhe-Arg-Phe-ProTGlyTArgTIle-AspT, Arg-IleTGly · β Ala — Phe — Arg — Phe — D — Pro — Gly — Arg-ile — Asp — Arg — Ile — Gly—

168 456

28. -Tyr-Ar g-P he-D-Ala-Gly-Arg-I le-Asp-Ar g-Ile-Gly-η. , -Tyr / Bzl / -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ille-Gly. -Phe-Arg-Tyr-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly- | and _________i. -Phe-Arg-Tyr / 3zl / -D-Ala-Gly-Arg “Ile-Asp-Arg-Ile-Gly

ί ......... 11 - -........ ................ ....... 1 ·

32. p β? Ala-Phe-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-Gly-i

- r ÓAla-Phe-Arg-BC-D-Ala-Gly-Arg-Nle-Asp-Arg-Ile-Gly and their salts.

Cyclopeptides of the general formula Ib should be distinguished

-A.-A _c -Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn-r i 4 i and their salts, where

A4 stands for Aund,

Aca, β-Ala

Clg, Thc, Btu or D-Btu,

A5 stands for Phe, D-Phe,

Phe / 4-NO2 /,

Ha,

Tire,

Tyr (Bzl) or a covalent bond;

Bn is Arg,

D-Arg,

Ctr,

Lys or a covalent bond;

Cn stands for Phe,

Ha,

Ser / Bzl / or uvi / j- / Z ί / uiuu

Tyr / Mr /;

Dn stands for D-Ala,

Gly or Azt;

En is Gly;

Fn is Arg or Lys;

Gn means Ile, D-Ile,

Met either

168 456

Nls;

Hn stands for Asp, D-Asp,

Gly or covalent bonds;

Tn b7 · naί ^ ’7A Aro- or D-Arg; and

Kn means Ile.

Especially preferred are uyclodhedtides or their sols in which

A4 is a ω-aminbalkanoic acid residue with weoaee -NH- / CH2 / 2-4-CO- or, when A5 is a benauea covalent bond, Clg, Thc, Btu or D-Btu;

A5 is Phs, Tyr, Cha, Nal or 4-NO2-Phs;

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

Cn is Phe, Cha, Tyr, Nal or Tsa (Bel);

Dn is D-Ala, Gly, Phe or D-Phs;

En is Gly or Ala; or

Dn and En together are D-Btu;

Gn and Kn independently of the sisbie represent Ile, Met, Nle or Leu; and Hn is Asp, Glu or Gly; especially those in which

A4 is β-Ala,

Apen or when A5 is a covalent bond, Clg, Thc, Btu or D-Btu;

And 5 is Phs,

Phs / 4-NO2 /,

Cha or Tyr; or

Bn is Arg;

Cn stands for Phe,

Ha,

Tyr or Tyr / Bzl /;

Dn is D-Ala;

En is Gly; or

Dn and En together are D-Btu;

Fn is Arg or Lys;

Gn stands for Ils,

Met or Nle;

Hn is Asp;

In is Arg; and

Kn means Ils.

The preferred compounds of the invention are:

1.- β> Ala-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-IlsAca-Arg-Phs-D-Als-Gly-Arg-Ile-Asp— ^: la-Phe-Arg- Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ils

4. -Aca-P'ne-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-,

168 456

5.- ', 6 Ala-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Aso-Arg-IleL Z:

_ Ch ai - / _n_- G._n> / _ i, ,,,, χν .H _C - ,. xy U. ^ 4. / - -u. ₇ .

-fil r, _ r ~ r. __ Λ -r.r ~ ._T 1 r, _ 'and X o - noj- »-." IX U - X X C'. -Aca-P he-Ly s-Phe-D-Ala-Gly-Ar g-Ile-Asp-Ar g-Ile- \

L ___ ί

3. -Aca-Phe-Lys-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-Ile9. ACaa-hhe-rgg-hha-D-Aaa-Gly-rgg-iee-spp-rrg-iee ^

- A c a - D — P e -— A r -— P hs — A * a-— dy — Ag 11 θ — A sp-A - ΐle-i l -----. - - - - --- - - - .. _____ _ - ___ i. r, A (^ i ^ pCh ^ · ^^^ ίrg · ^ |? hl-DpAIhpGllpArgpIllpAsppftr9pIllp

12. - β AIhpPhl · pAΓg-Clha-D-AIhpGllpArgpArgpIllpAsppArgpIllp _|

Ala-BC-Arg-Cha — D-Ala — Gly — Arg-He —- Asp-rre-H—> and

Alapphl / 4-NG2 / pArg-P he-D — Ala-Gly-Arg — Ile —- sp — Arg — Ilep

1-, j- ( ² } Ala-Phe-Lys-Cha-D-pAl ^ -GIy-Arg-Ill-AA □ pArg-IIe

16. pCIgpArg-ChhpDpAIapGIypArgpIIe-As □ pArg-IIe

17 p AIa-Phe / P-NG2 / -Arg-ChapDpAIapGllpArgpIle-Asp-Arg-IIep

18.- 2- AIapTlr / Bzl / pArgpCha-D-AIh-GllpArg-IlepAss-Arg-IIe

-LapTyrpArg-Cha-D-Ala-GllpAΓgpIllpAsppArgpIle-.

168 456

-Thc-ArgCha-D-Als-Gly-Arg-Ile-Asp-Arg-Ile

-) i- pAla-Phe-Ltr-Lha-u-Ala-uly-Arg-Ile-Asp-Arg-Ile

Thh c - P h ei - A r g - C h a - D - A1 a - G1 - - A g g - Ile - Spp- A r g -11 e -i

- Cl g-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-ile-η

Aund-Arg-Phe-O-Ala-Gly-Arg-He-Asp-Arg-I le- | prUnd-phe ^ 'Phe-O-Ala-Gl ^^ - / Arig- ^ IIe - AS-Arg-Ila

-Aca-Arg-P he-D-A.la-Gly-Lys-Nle-Asp-Arg-Ile—

-Aca-Arg-Seg / Bzl / -O-Ala-Gly-Ly s-Nl e-A sp-Agg-Il e-.

Aca-Phe-Agg-Phs-O-Ala-Gly-Lys-.NleAAggAIle

Ala-Phe-AΓg-phA-A-Ala-Gly-LyA -! 'Jle-AΓA-IeA

Aca-AggΓPhe-O-Ala-GlyΓLys-NleΓAg - Ile

AlaΓAg - Phe-O-Ala-Gly-LysΓ _l \ Jle-Agg-Ile .- β> Ala-Phe-Gly-Ser / Bzl / -O-Ala-Gly-Lys-Nle-Asp-Arg-Ile- η

A ca-Phe-Gly-Ser / Bzl / ΓO-AlaΓGlyΓLys-Nle-As-ΓAg - Ile

Ala-Gly-Ser / Bzl / -D-Ala-Gly-Lys .'le-A sp-Arg-ile

168 456

35.-Aca-Gly-Ser / azl / -D-Ala-Gly-t_ys-Nle-Asp-Arg-IleI

6 _ n, Slo- ^ q _er / B _z l / _ D_ A 1 _e _ Gl _y _ i., .--- 1 A _SS 36 »| yy 1. J. B Β Β X / BZI / D Ale Gly Lyc t * 1.CS ASU · ny— nc ir ·

37. _Aca_5er / 3zl / _D_Ala_Gly_Lys-Nle-Asp-Arg-Ile33. _ 3tu_Arg_P 'ne-D-.Ala-G1y-Arg-Ile -, -, sρ-AΓg-ϊ le .rD-3tu-Arg-, ^E he-D-Aaa-lyy-Arg-iee-Ssp-Arg- Ile40. _ AIa_AΓg_Phe_D_A1aeG1y_AΓgyIIe_ArgeIIe41. | eAca-AΓy_Phe_D-A1a_G1y-AΓy_I1e_Ary_I1e_ |

42. β AIayPhe_Ary-Phe_D_A1a_G1y_Arg_I1e_Ass_AΓg_3tu

43. _Aca_PheyArg_Phe_D_A1a_G1y_AΓgyI1e_GIyyAΓg_IIe »e · Aca-Phe-AΓg-Tyr / lee / -y-Aae-Gye-AΓe-Iee-Sse-Are-Iee. _A ca_Phe_Ary_Phe_D_Ala_Gl.y_Ary_D_Ile_A sseAΓg_I1e_]. .-Aca-Phey ^ Ar ^^^ P ^^ E ^ y ^ E ^ - / ^ I ^ ć ^ -GI ^ ¾ ^ - / ^ J ^^^ · ^ 1 ^ 3 ^! ^^ [^^ ί ^^ | 3 ^ <^ J ^ t ^^^ l ^ I ^ e. , -Aca_Phe_D_Ary_Phe-D-AIa_G1y-Arg-I1e_A ss_Arg_Ile

48. _AcayDyPheyAΓgyPhe_D_fi1ayG1y_AΓg_IIeyAssyAryyI1e. -Phe-AΓy_Phe_D-A1a-G1yy ^ AI ^^) ^] ^ I ^ E ^ - ^^^ f ^ y ^ A ' ^I? ^^^^ I ^ ^e

168 456 • d

50.- (β Ala-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

51. [- ίβ Ala-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

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

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

54. r- βι Ala-Phe-Arg-Cha-Azt-Gly-Arg-Ile-Asp-Arg-Ile55. .- ίβ Ala-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-.

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

57. -Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-j and their salts.

Mention should be made of the cyclopeptides of the general formula I and their salts, in which

An is H-Lys Z-Lys Bz-Lys Menoc-Lys / 4-NO2 / Z-Lys Bz-D-Lys Tos-Lys H-Dap or Z-Dap;

Bn is Arg,

Lys,

Phe or Om;

Cn stands for Phe,

Cha or Ser / Bzl /;

Dn is D-Ala;

En is Gly; or

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

Fn stands for Arg or

168 456

Lys;

Gn stands for Ile or

In is Arg; and

Kn means Ile.

Cyclopeptides or the salts thereof, in which

An is an aminoalkanoic acid residue of the formula -NH- / CH2 / _n -CH / R / -CO-, where n is 1 or 4, R is NHX or NXY, X is benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2- or 4- trifluoromethylbenzyloxycarbonyl, cyclohexyloxycarbonyl or methyloxycarbonyl and Y is benzyl or phenylethyl;

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

Cn is Phe, Cha, Tyr, Nal, Tyr (Bzl) or 4-NO2-Phe;

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

En is Gly, Ala, or Phe; or

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

Gn and Kn are independently of each other Ile, Met, Nle or Leu; and Hn is Asp, Glu or Gly;

especially those in which

An is H-Lys Z-Lys Bz-Lys Menoc-Lys / 4-NO2 / Z-Lys Bz-D-Lys Tos-Lys H-Dap or Z-Dap;

Bn is Arg, Lys, Orn or Phe;

Cn stands for Phe,

Cha, or Ser / Bzl /;

Dn is D-Ala;

En is Gly; or

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

Fn is Arg or Lys;

Gn is Ile or Nle;

Hn is Asp;

In is Arg; and

Kn means Ile.

The preferred compounds of the invention are:

. H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg. Z-L y s-Arg-P he-D-Ala-Gly-Ly s-Nle-A sp-Arg-Ile-.

. Z-Lys-Arg-Ser / 3zl / -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

168 456

4. Bz-Ly s-Arg-P he-D-Ala-Gly-L ys-Nle-A sp-Arg-Ile

7 ^ 1 * τ * ~ __D Ηζ-Π- A Ί »X <_1- I I I C · LJ - i t _i .n w. • Uj_ y. Z-Ly s-Arg-Cha-D-Ala-Gly-Ar g-Ile-Asp-Arg-Ile-i

7.Mengc-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-i

S. f-iengc-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile9. H-Ly s-Ly s-Cha-D-Ala-Gly-Ar g-I l e-A sp-Ar g-I l e-.

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

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

12. / 4-NC ₉ / Z-Ly s-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Ara-Ile-i I ³ _______1

13. Z-Lys-Crn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile. H-Lys-Arg-Phe-D-Ala-Gly-Ly si \ il eA so-Arg-Ile-j 1_ _: _!

15.h-Lys-Arg-Ser / Bzl / -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile-j

o. Bz-Ly s-Arg-P he-D-Ala-Gly-Ly s-Ml e-.A sp-Ar - l 1 e17. Bz-Lys-Arg-Ser / Bzl / -D-AlaeGIy-LyseNlleAsp-ArgeIlle

18. Bz-D-Lys-Arg-Ser / Bzl / -D-A la-Gly-Ly s-fll - A 5 - Αγ- ^ Ι1--.

19. TgseLys-AΓg-Phl-DeAIa-GlyeArg-IIseAsp-AΓg-IIl

168 456

20. H-Lys-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile 21. Z-Lys-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-i

22. Z-Lys-Arg-Cha-L-Clg-Arg-Ile-Asp-Arg-Ile23. Z-Lys-Arg-Cha-D-Clg-Arg-Ile-Asp-Arg-Ile-1

I_i. H-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-η i_____I

25. Z-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-A sp-Arg-Ile and their salts.

A distinction should be made between cyclopeptides of the general formula I and their salts, in which An is as defined above,

Bn is Arg,

Lys,

Phe either

Orn;

Cn stands for Phe,

Cha either

Cheese / Bzl /;

Dn is D-Ala;

En is Gly; or

Dn and En together mean

L-Clg or

D-Clg;

Fn stands for Arg or

Lys;

Gn stands for Ile or

Nle;

Hn is Asp;

In is Arg; and

Kn means Ile.

Particularly preferred are cyclopeptides and their salts, in which An is an aminoalkanoic acid residue of the formula -NH- / CH2 / _n -CH / R / -CO- in which n is 1 or 4,

R is -NH / H / -C / O / -CH2-X ¹ ,

-N / H / -C / O / -CH2-O-X ',

-N / H / -C / O / -X ',

-N / H / -C / O / -CH = CH-X ¹ or

-N / H / -C / O / -O-CH2-X ', where X1 is / a / phenyl, / b / by 1 or 2 substituents substituted phenyl, / c / 1- or 2-naphthyl, / d / 3-benzo [b] thienyl, (e) (2-pyridyl) or (f) (2-pyrazinyl);

168 456

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

Cn is Phe, Cha, Tyr, Nal, Tsr (Bel); or 4-NO2-Phs;

Dn means D-Ala. Gly, Phe, or D-Phe;

t?,., m oz ca .. «uKc; rm; ako dr νζ, ηανζ, α oi), ζ-νια, αιυυ r nc, αιυυ Dn and En together benace D-Btu, L-Clg or D-Clg;

Gn and Kn independently denote / Ile, Met, Nls or Lsu; and Hn is Asp, Glu or Gly; especially those in which

An is -NH- / CH2 / 4-CH / R / -CO-. where R is as defined above and Er-Fr-Gr-Hr-Ir-Kn are the chain -Aag-Cha-D-Ala-Gly-Arg-Ils-Asd-Arg-Ile- with particular reference to the examples.

The compounds of the invention are ANP-agonists. Like natural ANP, they have the following properties:

- specific and affinity binding to ANP receptors

- diuretic and saluretic properties

- blood pressure lowering effect

- increasing the hematbkiite

- increase in the plasma level of cyclic GMP / GMP: probably the intracellular hormone / second messengsr /, which can be detected in the plasma in greater amounts after administration of ANP /

- increased glomerular filtration

- vessel relaxing effect

- babnbuholityuene action

- sdcemiaing effect on smooth muscles, especially the intestines.

The properties of the compounds according to the invention are tested in individual cases as follows:

- Wi / ladies with ANP receptors

Ladies with ANT-receptors of Zona glbmerulosa cells from bovine adrenal glands are determined by the method of Biirgisser et al. / Biochem. Biohys. Rss. Commun. 133, 1201/1985 //, modified from Biirgisser / 2nd World Congress on Biblbgically Active Atrial Psptides, May 16-21, New York Am. Soc. Hydertens, Abstr. B181, pp. 209/1987 / using a commercial kit from ANAWA, Wangen, Switzerland.

- Lowering blood pressure, diurstic / salurstyuens effects, increasing hematokayt, increasing uyklb-GMP.

The research is carried out on anesthetized / Nembutal ^R / rats with spontaneous hypertension / lvanovas /. A cannula is inserted into the trachea. Blood pressure is recorded from A. Carotis by the pressure stress variator / Stathcm / on a recording device / W atcncbe Multiuoader /. The heart rate is calculated from the number of pulse waves per unit time. The substance is administered via a cannula to V. Jugularis. A cannula is inserted into the bladder through a small cut in the abdomen and the urine is collected. Urine volume is determined gravimetrically. Sodium and potassium are measured photometrically in a flame. khloask with the help of slsktromiαasczkbwanic. The hematocrit πιΐϋ « ^; out of arterial blood. Cyclic GMP is determined from arterial blood with the commercially available radioimmunoassay (IBL, Hamburg).

- Effect on glomerular filtration

Glomerular filtration is measured on the anesthetized dog and determined for inulin clearance by the standard method of Führ et al. /Wedge. East 33,729 / 1955 //.

- Loosening the vessels

The vasodilating effect analogous to ANP is determined according to the modified method of Faison et al. / Eur. J. Pharmacol. 102, 169 (1984) //. The thoracic aorta of the rabbit is pulled with the sudiamaximum concentration of serotonin. At 15 minutes after administration of the test substance, the narrowing of the serotonin bws is measured in comparison with the solvent control. The EC50 is determined graphically from the dose level.

168 456

- Broncholytic action

According to the method of Konzett and Rossler / Arch. exper. Path Pharmacol. 195, 71 (1940), the antagonization of histamine bronchospasm is investigated after intravenous administration of the test substance.

- Spasmolytic effect on the chicken rectum

According to the method of Currie et al. (Science, 221/4605, 71/1983) the spasmolytic effect on carbacholic stenosis of the chicken rectum is determined.

The compounds of the invention can be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, preferably with the aid of iontophoresis or potentiators known from the literature, and orally. For animals of various types of dose, which cause a significant reduction in blood pressure /> 20 mm Hg / and / or diuresis / + 300% / or saluresis / + 300% / and an increase in hematocrit / + 3% / and cyclic GMP / + 200% / , are between [mu] g / kg and 50 mg / kg. The doses for broncholytic activity in the guinea pig are in the same order of magnitude. Binding to ANP receptors in Zona glomerulosa cells of the bovine adrenal glands occurs with an IC50 between 1 · 10 ¹⁰ and 1-10 ^{· 5} mollOli tr. The vasodilating effect occurs on the rabbit aorta in vitro at an EC ₅₀ between 1 · 10 ^¼ and 1 10 ⁴ mol / liter. The concentration for the spasmolytic effect on the chicken rectum is of the same order of magnitude.

Since the binding of receptors by individual compounds according to the invention and ANP in terms of sfiy, are well correlated with the actions of biological litter, we can speak of the identity of the mechamism of the ρκηηκ'όζν peRy.ami occurring in nature and here based on them. T ^ u ^ spinning so wdtai zwuyzkdw the second aspect ^ wynąliyku potent expectations ^shaft rown © h ^ inn WTA ^- those wara biolg ^el zzy ^p o l ^{y c} opernych acłaaalgh ⁿ o ^ jrtydo ANR which 1u rzezagórowo not aostnta OPCs ano.

Pestle ^{and y} oi ^ k ztói domłaniu the compounds of the invention is comparable to the action of ANP. The order of the nets of vodlag ^, insisted on the size of the canΓtoazik. Prior technUó that rectangle moźm b ^ o by y / kowz ^{of, in} conjunction ^c c ązki so snacne ^and a mol wt mniojtzer wieUcoiści fo ^ ^ strive wykkk ⁱⁿ wί ^of dow y ^ d ^^ u from the deralania zo ⁿ owΓtażącej Da ^ U less więlkośai ozżsteczh ^e d ^ argument zwuizków c ^ u ^{0 e} ao ^COG cu ^m ojzyt above aaza ^l of pros tszz and kwienku the toźcz c ηϋ anaioze ANP ΚΛ paoóadaych ugNP and daZnm aiężaaan czerleuekowy rn ^y l ^y an ^a to ANP . ^wi s of ^d / ^a and energy are drawn poe u ^ c & ztów wyndazkm Ag / zwiarze for him ^± st doa / WZ composition ^A n ^ρi znacta thi ^{s t} ^ lciza than n; in ^ .νρη ^ υ. ANP derivative of ^a n ^{a h} Zbl complex to ANP. According to the Wynalzak in the late afternoon, ^a slw ⁱ h ^p o ANA nio na ^{w l} erąią mhrd ^ iów di ^ ihcz ^Z owyc ^c . by aa pu ^ s / a tah me ^z a ^a olicane sternness n stern from ANP i paahodn ^o lτi.

licked with ANta

The following compounds should be particularly distinguished, because their binding values with ANP / opistzntu receptors depend on the binding value of ANP / IC50 recuptorann this mmc ^ jzaa o ^and zc Ϊ0 * ζ mo ta.

Γ- ^k uΓl ^s -Phe-AΓg-Phe-D-Ala-Gly-AΓg-Ile-Asρ-AΓg-Ile-Gly- | | -Aca-Phe-Ar gP he-D-Ala-Gly-Arg-IIe-A sp-Arg-I le-Gly-i rA ca-P he-Arg-P he-D-Ala-Gly-Ly s -IIe-A sp-Arg-Ile-Gly

Ala-Phe-Ar g-P he-D-3 tu-Ar g-I le-A sp-Arg-I le-Gly- |

A la-P ne-Arg-P he-D-Ala-Gly-Ar g-11 e-A sp-Arg-I le-Gly-t

168 456

Phe / Ą-NCgZ-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Ara-Ile-Gly

Ald-Phe-Arg-phe-D-Ala-Gly-Arg-iMei-A sp-Arg-Ile-Gly la-Cha-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- Gly- y ¹ Ala-Phie ^ -NCg / -Ar ^^ | 3he-D-Al ^^ Gl ^) ^^ / ^ j ^^ - ^ sp-Arg-Ile-Gly- β Ala-Phe / 4— iNO2 / -A.rg-Cha-D-Ala-Gly-Arg-Ile-Asp-Ar g-Ile-Glyλ Ala-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Aro-Ile -Gly-,

Lf βAlaT | yr / 3zl / -Arh ~ CDa-D-AlG-yiy-Arg-iee-Asp-Arg-Ile-Gly

Apen-Phe-Arg-P he-D-AlaAG-y-AΓg-IleAAsp-AΓgAI-e-Gly ίlAb ^ JL-Phe-AΓg-PheADAA-a-Gly-AΓg-I-eAAspAArg-Ile-G-y

-Gly-P he-AΓg-PheADAAlaAGlyAAΓgA-leAAsp-AΓgA-le-G-yΗ ββ Ala-PheAAΓg-phe-DAβtuAAΓg ^ I-eAAsp-AΓg-I-eAGlyA l ’_ _ _!

β Ala-PheAAΓg-Phe-PΓo-Gly-AΓgAIIeAAspAAΓgAIle-Gly ρ β AlaAphe-Arg-Phe-D-Pro-G-yAAΓgA-le ^^ sD - ^^^^^ - eAG-y- ₁

Li _: _ i pTy ^ A ^ -Phie-D-Ala-Gly-Arg-Il e-A spAArgAIle-GlyA

Tyr / 3y: l / -Arg-Phe-D-Ala - Gly-Arg — Ile — Asp — Arg-Ile- Gly32

168 456 —PheTArg-Tyr — DTAla-Gly-Arg — Ile — Asp — Arg-Ile-Gly p h ~ Γ I IC

A -. - T. ^ / D - Ii / D AT - m .. A - - U - A__

-nx y— i y x / u x x / - u — η χσ - ui y - nx y— χ χ β — η & μ * nx ym y.

• ux y · rl

Ala-Phe-TArg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-Gly—.

- β Ala-Phe-Arg-PheTD-. Ala-Gly-Arg-Nle-Asp-Arg — Ile-Gly

L!

| - β Ala-Arg — Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-IleAca-Arg — Phe-D — Ala-Gly-Arg — Ile-Asp-Arg-Ile 'β Ala-Phe- Arg-Phe-D-Ala-Gly-ArgTle-Asp-Arg-Ile-.

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

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

Ala-Phe-Arg-Ser / BzΊ / -D-Ala-Gly-Lys-Nls-Asp-Arg — Ile pAca-Phe — Lys-Phe-D-Ala-Gly — Arg — Ile-Asp-Arg — Ile— r-Aca-Phe-Lys-Phe-D-Ala-Gly-Ly s-Ile-Asp-Arg-Ile-Aca-Phe-Arg-Cha-T-lla-Gly-Arg-IlT-ssTAArT “llT-, ! _________ [

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

T.

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

168 456

Ala-Phe-Arg-Cha-D-Ala-lly-Arg-Ile-Asp-Arg-Ile-,

SlaePhigSAggChapDgSlagGlygSAggMitgSASgSAg ^ II ^ i

Ala-Phe / l-NC ^ / - Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

Ala-P he-Ly sC ha-DD-Aa-Gly-AAg-Ile-A sp-A.rg-Ile g —Ala-Phe / 4 — NO ₉ / -Arg-Cha-D-Ala-lly-Arg -Ile-Asp-Arg-Ile lj:

SlaeTyr / BzlXgAAggChagDgAlagGIygAAggIllgAss-SAg-Ile

SlagTyAgSAggChagDgSlagGlygSAggIllgAASg-AggIll

SlagPhlgCtAgChagDgSlagGlygSAgglllgSAS ^ S ^ A ^ ę ^ - ^ I ^ I ^ t ^ gThc-PhieSrg-Cha— \

Dp

Sla pGIygSAgpIIlpAASgSAggIll gSundgSAggphieD-Sla-Gly-Arg-Ile-Asp-Arg-Ils

AundpphlgSAggPhlgDgAlapGIypAAgpIIlpAASpAAgpIll gAcapŚAgpphlg □ pSIagGIypLyApNIlg-sspAAgpIll

P ca-Argg5iAX Bzl / gDgSlapGlypLyApNllpAASgAAgpIllg gBtUgAAggPhlgDg-lSgGlygSAgpIllgS AS-SAgpIl e-j

Dp3tu-SΓgpPhlgDpAlagGlypSAgpIllpAASpSAgpIllg,

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

-Aca-Phe-Arg-Tyr / Me / -D-Ala-IAAr ^^ Il ⁸ Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-D-Ils-A sp-Arg-Ile

Aca-Phe-ArgΓphe-DΓAla-Gly-Arg-Il ^ - ^^ - ^ A £ ^ p ^ Ar9-I] ^ e

ΓAcaΓPheΓDΓArg-Phe-D-Ala-GlyΓArg-Ile-Aί ^ pΓArgΓIle —A ne-O-A la-Gly-Arg-IleA, s pp-Agg-iee

-laΓPhlΓ-Γg-Phg-DΓ-laΓGlyΓ, -rgΓIllΓAspΓD-Arg-Ile

AlaΓPhl-D-AΓg-PhlΓDΓ-la-Gly-ArgΓIll - sp-AΓg-Ile

HΓLys-Arg-PhlΓDΓAl3-Gly-Ls s-He-A sp-Ar g-Ile -η

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

Z-Lys - rg-Se: ^) ^ l3zl) ^ - D ^ Ala-Gly-LyA-Nll-AAp-ArgΓIlln

Bz-Lys-ArgΓPhl-D ^AlaΓGly-Lys-Ill - Ap-Arg-Ile–.

i_1_1

Z-LyA-ArgΓPhl-D sAla-Gly-Arg-Ill-Asp-Arg-Ill (_1 __________ 1

Z-LyA-ArgsCl ^ a-DΓAlaΓGly-Arg-Ile - sp-Arg-IllΓ s___I

Mlnoc-LyssArgsPhe-D-Al ^ sGly-AΓg-Ils-Sps-Ags-Ies

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Msnoc-Lys_AΓg-Cha_D_A1a_G1y-Arg_IIs-Asp-Arg-Ile

AND_

H-Lys-Lys-Cha-D-Ala-Gly-Ara-Ile-A ss-Arg-Ilι: '

Z_Lys_Lys_Cha_D_A1a_GIyyAΓa_I1e_Ass_AΓgyI1e / 4_NG / Z_Lys_ArQ_Cha_D_Ala-Gly_Ara_Ile_Ass_Ary_Ile ² i _: _: _; _

Z-Lys_Qrn_C'ha_D_A1a_GIy-Arg_I1e_Ass_Arg_I1sH-Lys_Arg_Ser / Bzl / _D_Ala-Gly-Lys-Nle-Ass_Arg-IleBz-Lys-Arg-Pte-D-Ala-Ala-Gly-Ass-Lys-Gly-Ass

Bz-Lys-Arg-Ser / Bzl / _D_Ala-Gly_Lys_Nla_Ass_Arg_Ile_ ₁

Bz-D-Ly s-Arg-Ser / Bzl / yD_A1a_u1y-Lys_N1e_Ass-AΓg-I le-i

Tos-Lys-Arg - P te e - D - A1 a - G1 y - A r g -11 e se-Age-Iee

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

Z-Lys_Arg-Phe_L_Clg_Arg_Ile_A ss_Arg_Ile

Z_Ly s_Arg- Cha-L — Clg — Arg — Ils — A ss — Arg— Ile-s

Z-Lys_Arg_Cha-D-Clg_Arg-Ile ss-Arg_Ile

ZyDap_AΓg_Cha_D_A1a_G1y_AΓg_I1s_Ass_AΓg_Ile

168 456/4-NO ₉ / Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ret-A sp-Arg-Ileη i____I / 4-NO 2 / Z-Lys-Orn-Cha-D-Ala -Gly-Arg-Ile-Asp-Arg-Ile-j 1_______ _1 x2-Lys-Ara-Cha-D-Ala-Gly-Arg-Ile-A sp-Arg-Ile-j i ~ '-1 where x2 is one of the following groups

168 456

On the basis of the scope of action of the drugs according to the invention, they can be used as antihypertensive agents, as vacuum agents, as diuretics, for circulatory improvement (vasoconstrictive action), e.g. V-ł maunrrlz-klnrar zm ρ-ιΛη 'm.n''' * Cł icvz.cina mv wy uvmv ^ zc ovnzu, uiv * »j nuv ^ jh miv ^ vwj vu, mv wy uiBiiiBooi niMZ ^ gUnuna ^, uesnibwej, renal failure, acute renal failure, and in the case of edema of any epibdeenia, e.g. cerebral edema, as well as in the case of cirrhosis of the liver, as relaxation agents for all organs with smooth muscles, especially the cystic / intestinal system, including the gallbladder and organs with urinary drainage and as bronchial drainage agents.

In addition, they can be used in the diagnosis of images of given diseases, as well as for the examination of the systems of the administered organs. Furthermore, they can be used as auxiliaries for the production and purification / specific sampling chromatography / antibodies or πα-receptor preparations in immunoassays / e.g. RIA, ELISA / and receptor binding tests / e.g. tsst with a radiation receptor 'like specific and selective ligands.

Compounds of general webase I can be used as medicaments and scarπcceutaneous preparations containing ts compounds. Advantageous use in humans.

For parenteral administration, the compounds according to the invention are brought into a solution, suspension or emulsion together with the substances usually used, such as dissolving agents, emulsifiers or other auxiliaries. Solvents used are, for example, water, physiological saline or alcohols, e.g. ethanol, dabdcnediol or glycerin, sugar solutions, such as glucose or mannitol solutions, or a mixture of different solvents.

In addition, the compounds can be administered by means of implants, e.g. from polylactide, dbliglycolide or pblihydroxybutyrate. Other application options are epicranial administration, inhalation administration, (diszb-spreot, dosing aerosol, powder inhaler), dbdaskin application (plastrows, creams, ointments, gel, passive plaster, whereby the effect can be enhanced with a penetration enhancer and /) or by means of an electric field (iontophoresis), oral administration (tablets, capsules, dragees, etc.).

The compounds of the general formula I can be used as components and intermediates in the above-mentioned biochromatography, biotechnology and immunological methods / production of piecemeal, specific loading chromatography. RIA, ELISA, tsst with radiation receptor /.

The compounds of the invention can be prepared according to generally known methods of peptide chemistry. Such methods are described in Houben-Weyl, Methoden der oaganisuhen Chemie vol. 15/2. Preparation according to peptide synthesis in solid fc / e.g. G. Barany, R.B. Msarifield in The Peptides-Abalysis, Synthesis, Biologt, Vol. 2, 2-284 (1980), Academic Press, New York, or R.C. Sheppard, Int. J. Pspt. Prot. Rss. 21, 118/1983 / or by equivalent known methods. As protecting groups for the amino group, the groups described in Houben-Weyl, Methoden der baganischen Chemie vol. 15/1 are used. Preference is given to using urethane protecting groups, such as e.g. In order to prevent side reactions, the swsntually present groups in the amino acid side chains are usually additionally protected with suitable protecting groups (see, for example, Houben-Weyl vol. 15/1 or T.W. Greene, Protecting Groups in Organic Synthesis). These include Arg (NO2, Arg (di-Z), Arg (Pmc), Arg (Mtr), Tyr (tBu), Tya (Bel), Tyr (2,6-dikl-Bel), Ser (tBu) , Ser / Bzl /, Asp / tBu /, Asp / Bzl /, Glu / tBu /, Glu / Bzl /, His / Tat, His / Bum /, Lss / Boc /,

Lss · / Z /, Z-Lys, Orn / Bbu /, Dcp / Bbc /, Hbmb-Aag / Mta /, Homo-Arg / Pnc /, Homo-Arg / NO 2 /.

For the synthesis of compounds of general formula I according to solid-phase synthesis, polystyrene, polyacamide and dblietea-based resins are used. For the synthesis of uyclb-peptides, it is preferred to use functional groups which give peptide carboxylic acids on desiccation. Particular preference is given to using functional groups which cleave eauhodei under conditions so mild that the swsntually obscns protecting groups on the side chains remain intact. When using Fmbu-stratsgii, the following functional groups are considered: 2-mstbkss-4-clkokssrenzslowsgo alcohol group / MMergler et al., Piouesdings of the 10th Amsrican Peptide Symposium 1987, St. Louis, p. 259, G.R. Marsh, EdEscom, Leiden (1988), hs-hydroxy-tronoylamidebmethyl (H. Kunz, BOombo, Angsw. Chem. Int. Ed. Engl. 27,

168 456

711 (1988) or a trialkoxybenzhydryl alcohol group (H. Rink, P. Sieber, Peptides 1988, p. 139, G. Jung, E. Bayer Eds., W. deGruytter, Berlin 1989).

Cleavage of the amine protecting group for the Boc group is carried out with trifluoroacetic acid in dichloromethane or, in the case of the Fmoc group, preferably with organic bases, especially amines, such as, for example, piperidine or morpholine in DMF or N-methylpyrrolidone (NMP). Usually a concentration of 20 to 50% of the base in the solvent is used, the reaction time is 10-120 minutes. Preferably the cleavage is carried out in two steps, the first reaction time being about 3 minutes. The resin is then washed briefly with the solvent. Thereafter, a further cleavage is carried out with 20% piperidine in DMF, the solution is then sucked off and the resin thoroughly washed with the solvent. Preferred solvents for these washing steps are DMF, NMP, dichloromethane, trichloromethane, methanol, ethanol, isopropanol, water, and tetrahydrofuran. After complete removal of piperidine, Fmoc is attached - an amino acid needed for the next coupling. This cycle is repeated sequentially until the desired resin bound peptide is formed.

Methods known in the art of peptide chemistry can be used for coupling (see Houben-Weyl, Methoden der organischen Chemie vol. 15/2 /). Carbodiimides are preferably used, such as, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, ethyl-3'-dimethylaminopropyl) -carbodiimide or hexafluorophosphate or O-benzotriazol-1-yl-tetramethyluronium tetrafluoroborate (R). Knorr et al., THL 30, 1927/1989 // or benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate / B. Castro et al., THL 1975.1219). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOOBt), racemization can optionally be reduced or the reaction rate increased. The amino acids Asn and Gln are preferably coupled in the form of their N-protected p-nitrophenyl esters. The coupling is typically performed using a 2-5 fold excess of the N-protected amino acid and a coupling reagent in solvents such as dichloromethane, dimethylformamide, N-methylpyrrolidone (NMP) or mixtures thereof. The course of the coupling reaction is checked by the Kaiser / E test. Kaiser et al., Anal. Biochem. 34, 595 (1970) or the TNBS test. If incomplete acylation is found, the coupling is repeated until successful. Solid phase synthesis can be performed both manually and automatically with a peptide synthesizer.

The thus synthesized linear peptides are then cyclized by appropriate methods known from the literature. The substances used for the coupling of the amino acids or the pentafluorophenyl ester (DMAP) or the diphenylphosphorylazide (DPPA) can be used as cyclizing agents. For the synthesis of compounds of general formula I, preferably a solid phase synthesis according to Fmoc-strategy using a functional group of 2-methoxybenzyloxybenzyl ester. The DCC / HOBt, DIC / HOBt or TBTU method is preferably used as a coupling method for building the sequence. After building up the sequence on the resin, the N-terminal Fmoc group is cleaved off in a known manner, the resin, after removal of piperidine, is thoroughly washed with dichloromethane and then treated with 1% trifluoroacetic acid in dichloromethane to detach the peptide. The protecting groups in the side chains of the peptides remain unaffected. After distilling off the solvent, the peptides are reacted with a cyclizing agent, preferably diphenylphosphorylazide, to give the corresponding cyclopeptides. Subsequently, any side chain protecting groups still present are removed with suitable cleaving reagents. Preference is given to using mixtures of trifluoroacetic acid with a scavenger.

Suitable scavengers are preferably substances such as, for example, anisole, thioanisole, cresol, thiocresol, ethanedithiol, water or the like, and mixtures of such scavengers. The peptides are then processed and purified by methods known in the art of peptide chemistry.

Purification of the crude products obtained is carried out by means of gel permeation chromatography, e.g. on Sephadex G25 / MR < 1400 / or G15 / MR < 1400 / with 1% or 5% acetic acid. If desired, further purification is carried out by preparative

RP-HPLC using methanol- or acetonitrile-water gradients with 1-2% trifluoroacetic acid.

168 456

You can also use substances that are exchanged for SephaCex or pulisayrene powder.

The onzheanzoaie is preferably carried out after a frosted HPLC with a frosty phase deposited in a woCo ^/ oceioniiohl gradient with dudaantham 0.1-0.2% iriflauroontoma, gu.

The compounds of formula I are simply separated by RP-HPLC. Each time, the analysis of avo acids is carried out on the ion exchanger (LKB /) and on the neomographs in the trait column in order to duCatcome oacemtaanji.

In addition, the 13C-NMR spectrum (Boukeo 400 MHz / uraa FAB mass spectrum (FianiganMAW 90) is obtained. The determination of the sequence follows the pumona sequwaAcjunomaata in the gaauwa phase after the trhptnnznhm dispersed epiaAia.

The following words explain whAalaan's synthesis of tensions, they do not limit his strain.

Example I.

Ala-P he-Arg-P he-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-j

ShAtaaę pepihCa is carried out in the ACVΓAned ChemWana papthCuwym ACW200 shntażorek with zaetosumoaiam Fmon-strategie and aΓetusowoaiaw wuCyfinumoaeau steoującegu program. 50 wl of reonuo wettraąeΓAy are filled with 1 g of the 2-matokey-bunkyl ester of the Bachem, Sawajcoria, nΓehnonej 0.5 wola Fmon-glichnh company. He uses the following avinoCna ponos: Fmon-Ila-OH, Fwoc-Aog / Mtr / -OH, Fwon-Asp / tBa / -oH, Fmoc-Gly-OH, Fmon-D-Ala-OH, Fwun-Pąe-OH and Fmun-βAla-OH. Couplings lead to zoetosuwoataw excessively 3 mAUWΓdAtnóm Fmon-ΓmtnokmΓeu, 1-hyWoksybenaoiriożula i cśiny0luheksylokoobudiimidu / caae sporoaoaia 40 minutes /. After carrying out the WNBS test with complete onhlumania, conjugation with a sufficient amount of these owl reagents and peroxides is carried out. In the item / poWAu nałnuwitago ΓnyłuwaAia rozunahAO the next cycle of shnteah takes place. Caiacininization of Fkoc groups was performed overCooaaomo with 20% piperidine in DMF (oaz 3 minutes, once 15 minutes). Repeated reoncernment of the wine was washed with the urine of 10-ntrotate DMF. After abuduwoAia, the sequence of H-βZla-Pąe-Aog / Mto / -Phe-D-Ala-Gly-Z.og / Mto / -Ile-Zsp / tBU / -Zog / Mto / -Ila-Gly - on a potable resin carrier the mixture is soaked in dichloromethane and then Ζογ 5 times with 20 ml of a 1% solution of toifluuroocaumeao acid in Cinchlorination for 10 minutes at room temperature / until an intimate lilac color /. The solutions are combined and concentrated in vacuo. PuzostaleZU is triturated with ether, ether Cekantuja, pepahd is dried in digestion of aaota and πΑπ ^ ο in 130 ml of DMF, the pH value is about 8.5 with triethylawinh, ο ^^ οο cooled to -20 ° C and CoCaje 0, 2 g / 0.75 wwoli / Cifenhlofusfurhluazydek. The mixture was allowed to settle for 48 hours at -20 ° C at water temperature and at 4 ° C for 48 hours. WaoZuśU pH is equal to aa 8.5 after toiatil, oamma. The DMF is then removed in vacuo, left to roacar with ether twice, the ether is added to it, and the residue is dried in aaota stream. Side-chain protecting groups are followed by toiflaorouctuwaao / aniaulu / 90/10 / acid flush for 24 hours in iampaoatuoae peace. The solution was soaked in vacuo, the residue was triturated with ether and sasah. Raw paptyC is analyzed on 3μ-culumnte / 10 x 2.14 cw / with Dynamo * C18 with a gradient transition from A: modΓ / anetonitohl / kmas toifluorouna 95/5 / 0.2 and B: dito 20/80 / 0.2 from 10% B to 80% B in 11 minutes, stream 20 l, on a retention of 6.01 minutes. After drying, an amorphous colorless powder is obtained. FAB-MS / M + H / + = 1360.5.

Example II.

, -Aund-O he-Arg-P he-D-Ala-Gly-Ar gI le-A sp-Arg-I le-GlyZ aasiusowantam Fmoc-Aund-OH instead of Fwun-βAlo-OH will remain as described in the example I crude peptide which was purified by dry purification using σpisanynh maounkóm chromatography (5% by 80% B over 11 winutes, retention time 7.45 miau).

FAB-MS / M + H / + = 1473.2.

168 456

Example III.

-A _C aePhl-.Arg-Phe-D-Al ^ -GIyeArg-IIl-Asp-Arg-ΐle-GIy- |

Using Fmoc-Aca-OH instead of Fmoc-Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% 80% B in 11 minutes, retention time 6.00 minutes /. FAB-MS / M + H / + = 140C, 1.

Example IV.

.-Aca-Phe-Arg-Phe-D-Ala-Gly-Ly s-Ile-Asp-Arg-Ile-GlyZ using Fmoc-Lys / BOC / -OH and Fmoc-Aca-OH instead of Fmoc-eAla-OH replaced The crude peptide is purified as described in Example 1, which is purified using the chromatography conditions described, 15% / 80% B in 11 minutes, retention time 5.80 minutes).

FAB-MS / M + H / + = 1C74.9.

Example V.

- β βIaePhe-Arg-PhleD-Btu-ArgeIIl-Asp-Arg-I-le-Gly-j

Using Fmoc-D-Btu-OH instead of Fmoc-D-Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% B, 80% B in 11 minutes, retention time 6 .05 minutes /.

FAB-MS / M + H / + = 1C72.7

Example VI.

.- / 4-MO2 / -Phe-Arg-Phe-D-Aaa-Gly-Ar g-Ile-Asp-Arg-iee-Gyy-.

Using FmocaPhe / 4aNO2 / -OH and without Fmoc-β-1aaOH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described, 15% by 80% B in 11 minutes, retention time 6.45 minutes /.

FAB-MS / M + H / + = 1CC4.9.

Example VII.

IP βAa-Phz-Arg-Phe --- AAa-Gly-Arg-Net-Asp-Arg-Ile-Gly By additionally using ^ α-Met-OH, a crude peptide is obtained as described in Example 1, which is purified using chromatography conditions (5%, 80% B in 11 minutes, retention time 6.10 minutes).

FAB-MS / M + H / + = 1C78.8.

Example VIII.

- βAla-Cha-Arg-Cha-D-AlaLi

Gly-Arg-Ile-A sp-Arg-Ile-Gly

Using Bmoc-Cha-OH instead of Fmoc-Phe-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% 80% B in 11 minutes, retention time 7.75 minutes /.

FAB-MS / M + H / + = 1C7C, 0

Example IX.

β A IaePhl / -t-KO2 / eArgePhl-DeńIaeGIy-Arge-IeeAsp-Arge-Il-Gly-.

168 456

Using Fmoc-Phe (4-NO2 / -OH), a crude peptide was obtained as described in Example 1, which was purified using the chromatography conditions described (5% of 80% B in 11 minutes, retention time 6.50 minutes) .

C A B Male / MxU / x - 1 ΛΓ6Ζ O

Example X.

β Ala-Phe / 4-NC ₂ / -Arg-Cha-D-Ala-Gly-Arg-He-A sp-Ar g-Ile-Gly With Fmoc-Cha-OH instead of Fmoc-Phe / 4-NO2 / - OH instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1, which was purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 7.40 minutes).

FAB-MS / M + H / + = 1412.0.

Example XI.

βl ^ -Tyr-Arg-Chιa-D-Ala-Gly-Arg-Ile-Asp-Arg-ΐle-GlyZ using Fmoc-Tyr / tBu / -OH and Fmoc-Cha-OH instead of Fmoc-Phe-OH is obtained in as described in Example 1, a crude peptide which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.40 minutes).

FAB-MS / M + H / + = 1383.2.

Example XII.

Ala-Tyr / Bzl / -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly With Fmoc-Tyr / Bzl / -OH and Fmoc-Cha-OH are prepared as described in the example And the crude peptide which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 8.50 minutes).

FAB-MS / M + H / + = 1473.2

Example XIII.

-Aca-Phe-Arg-Phe- £? Ala-Arg-Ile-Asp-Arg-Ile-Gly Using Fmoc-Aca-OH and Fmoc-βAla-OH, a crude peptide is prepared as described in Example 1, which is purified using the chromatography conditions described / 20% by 80% B within 10 minutes, retention time 4.60 minutes /.

FAB-MS / M + H / + = 1345.9.

Example XIV.

, -Aca-Phe-Arg-Phe-AAuu-AAg-IIe-Asp-Arg-Ile-GlyZ using Fmoc-Aca-OH instead of Emoc ^ na-OH and Fmoc-Abut-OH is prepared as described in example I crude a peptide which is purified using the chromatography conditions described (20%, 80% B in 10 minutes, retention time 4.85 minutes).

FAB-MS / M + H / + = 1373.8

Example XV.

-Apen-P he-A rg-Phe-D-AAa-GGy-AAg-Il s-A 30-, ^ O-Ile-Gly-.

Using FmocIApenIOH instead of Fmoc-βAla-OH, a crude peptide was obtained as described in Example 1, which was purified using the chromatography conditions described (20% for 80% B in 10 minutes, retention time 4.50 minutes).

FAB-MS / M + H / + = 1388.8

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Example XVI.

(p S b u t g P hieftAgep hlgD - lagGly-ArggIllg-ASg-AggIll-Gly

Using Fmoc-Abut-OH instead of Fmoc-Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 20%, 80% B in 10 minutes, retention time 4.35 minutes /.

FAB-MS / M + H / + = 1374.8

Example XVII.

^ Gl / pPhl - Γg-Phl-D ^ Ala-Glyg-rg-Illg-Apg-rg-Ill-Glyg |

Using Fmoc-Gly-OH instead of Fmoc-Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 20%, 80% B in 10 minutes, retention time 4.45 minutes /.

FAB-MS / M + H / + = 1346.8

Example XVHI.

β; PlagArggphl-D - l3-Glyg-rg-Ill-AASgAAggIllgGly

Using the Fmoc-amino acids described in Example 1, a crude peptide is obtained which is purified using the chromatography conditions described (20%, 80% B in 10 minutes, retention time 3.25 minutes).

FAB-MS / M + H / + = 1213.8.

Example XIX.

_Γ Acag-AggphlgDgAlagGlygAAggIllgAASgAAggIllgGlyp ^

Using Fmoc-Aca-OH instead of Fmoc -— Ala-OH as described in Example 1 a crude peptide is obtained which is purified using the chromatography conditions described / 20% for 80% B in 10 minutes, retention time 3.45 minutes /.

FAB-MS / M + H / + = 1255.8.

Example XX.

{pAundgAΓggphlgDgAla -Gly - ΓggIll - AS-AΓg-Ill-Glyp |

Using Fmoc-Aund-OH instead of Fmoc -— Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 20% for 80% B in 10 minutes, retention time 5.15 minutes /.

FAB-MS / M + H / + = 1325.8

Example XXI.

reAcagphl-Ar g-Phe-AocgAΓggIllgA Ap - rggIlep ^ G ^ l ^ y ^ -l

Using Fmoc-Aca-OH instead of Fmoc -— Ala-OH and Fmoc-Aoc-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% by 80% B in 11 minutes , retention time 7.10 minutes /.

FAB-MS / M + H / + = 1416.2

Example XXII.

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

168 456

By additionally using Fmdu-Aib-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 5.70 minutes).

FAB-MS / M + H / + = 1217.8.

Example XXIII r- -IasPhls-ΓgsPhlsDs-IasGIys-ΓgsTIls-ibs-rgsIIlsGIyΓ

Using Fmoc-Aib-OH instead of Fmdu-Asp / tBu / -OH, a crude peptide was obtained as described in Example 1, which was then dispersed using the chromatography conditions described / 35%, 65% B in 3.5 minutes, time retention 3.70 minutes /.

FAB-MS / M + H / + = 1330.9.

Example XXIV.

-β -lasPhlsArgΓPhe-L-Btιn-AΓg-Ile-Aρp-Ags-IlsGllsη

Using Fmdc-L-Btm-OH instead of Fmdc-D-Ala-OH, a crude peptide is obtained as described in Example 1, which is disintegrated using the chromatography conditions described, 15% Btm 80% in 11 minutes, retention time 5 ,90 minutes/.

FAB-MS / M + H / + = i 372.7

Example XXV.

- SIasphls-rgΓphssDs ^ tιτιs-rgsIIlΓ- _S ps-rgsIIlsGIys

By using Fmoc-D-Btm-OH instead of Fmou-D-Ala-OH, a crude peptide is obtained as described in Example 1, which is then obtained using the chromatography conditions described / 5%, 80% B in 11 minutes, retention time 6.05 minutes /.

FAB-MS / M + H / + = 1372.0.

Example XXVI.

- β -Iasphls-rgsPhlsProsGIys-, ΓgΓIlls- _S p_- _Γ g _; [l _e _Gly_

By using Fmdu-Prd-OH instead of Fmou-D-Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% B, 80% each in 11 minutes, retention time 6. 15 minutes/.

FAB-MS / M + H / + = 1386.8.

Example XXVII.

- β -IaΓphls-ΓgsphlsDspΓ _O sGIys-rg-ϊIls- _S ps-rgsϊIlsG; ly.,

Using Fmoc-D-Pro-OH instead of Fmoc-D-Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5%, 80% B in 1 minute, time retention 6.35 minutes /.

FAB-MS / M + H / + = 1386.8.

Example XXVIII.

sTyr - Γg — Phl-DΓ-la — GlysArgsIIlΓ-sp-Ars — Ill — Gly By additionally using Fmoc-Tyr / tBs / -OH and without Fmoc-pAla-OH, a crude peptide is obtained as described in Example 1, which is altolating the chromatography conditions described (5% after 80% B in 11 minutes, retention time 5.40 minutes).

FAB-MS / M + H / + = 1306.0.

168 456

Example XXIX.

_| τTyr / Bzl / · τArg-Phl-D-AlaτGlyτAΓgτIleτAspτArgτIllτGlyτ

By additionally using Fmoc-Tyr / Bzl / -OH and without F6 [alpha] -AAI-, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% by 80% B in 11 minutes. retention time 6.10 minutes /.

FAB-MS / M + H / + = 1395.9.

Example XXX.

_phe-Arg-Tyr-D-Al3-Gly-Arg-Ile-Asp-Arg-Ile-GlyT

By additionally using Fmoc-Tyr / tBu / -OH and without Fmoc-AAla-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% by 80% B in 11 minutes, time retention 6.55 minutes /.

FAB-MS / M + H / + = 1305.9.

Example XXXI.

^τ Ph ^lτ A ^r gτT ^y r / Bzl / τ ^D τ ^Al 3τG ^l yτArg ^τ Illτ ^A sp ^τAr 9 ^τIllτ C ^l y ^τ .

By additionally using Fmoc-Tyr / Bzl / -OH and without Fmoc-AAla-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% by 80% B in 11 minutes, time retention 7.10 minutes /.

FAB-MS / M + H / + = 1395.9

Example XXXII.

Ala-Phl-ArgτPhl-L-Clg-ArgτIll-AspτArg-Ile-Gly-:

Using Fmoc-L-Clg-OH instead of Fmoc-D-Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5%, 80% B in 11 minutes, retention time 6.90 minutes /.

FAB-MS / M + H / + = 1400.8

Example XXXIII.

AlaτPhl-AΓg-Phl-DτAlaτGlyτArg-NllτAsg-Arg-Ile-gly—

By additionally using Fmoc-Nle-OH as described in Example 1, a crude peptide is obtained which is purified. using the chromatography conditions described (5% 80% B in 11 minutes, retention time 6.40 minutes).

FAB-MS / M + H / + = 1360.4

Example XXXIV.

p

- 3) TlaτPhl-Arg τChaτD-Ala-GlyτArgτ | 'lltτAspτArgτIllτ

Peptide synthesis is performed using the Advanced ChemTech ACT200 peptide synthesizer using Fmoc-strategy and a modified control program. A 50 ml shake reactor is charged with 1 g of 2-methoxybeazyl ester resin from Bachem, Switzerland, saturated with 0.5 mmol Fmoc-isoleucine. The following amino acid derivatives are used: Fmoc-Arg / Mtr / -OH, Fmoc-Asp / tBu / -OH, Fmoc-Met-OH, Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc-Cha-OH, Fmoc-Phe-OH and Fmoc-AAla-OH. Couplings are performed using 3 equivalents of Fmoc-amino acid, 1-hydroxybeazotriazole and dicyclohexylcarbodiimide each (40 minutes coupling time). Following the TNBS test, the coupling is repeated using the same reagents and excesses in the event of incomplete acylation. In the event of complete acylation, the next cycle begins

168,456 syntheses. The cleavage of the bchionnyuh Fmoc groups is carried out each time with 20% piperidine in DMF (once 3 minutes, once 15 minutes). The resin is washed 10 times with DMF between the reactions. After building a linear sequence of H-βAlα-Phs-Aig / Mtr / -khτ-D-Ala-Gly-Ag / Mto ^, -Met-Aid / tBu / Aag / Mta / -Ile- on pblim. no dichloromethane and then treated 5 times with 20 ml of a 1% solution of taίphic acid (rrooctbvic acid in dichloromethane for no more than 10 minutes at room temperature (until the resin is intensely colored). The solution is combined and concentrated in vacuo. The residue is roecisic, the rudder is decanted, the p-peptide is dried in a stream of nitrogen and taken up in 130 ml of DMF, the pH is adjusted to about 8.5 with triethyl ° C, the solution is cooled to -20 ° C and 0 is added. , 2 g (0.75 mmol) of diSenylSbsSorylbazide The mixture was allowed to stand for 48 hours at -20 ° C and 48 hours at 4 ° C. The pH was maintained at 8.5 with triethylamine. The DMF was then removed in vacuum, the residue is triturated twice with ether, the ether is decanted and the residue is dried under a nitrogen stream. the side panels are detached with trisorbutic acid (anisole (90/10) for 24 hours at room temperature. The solution was concentrated in vacuo, the residue was triturated with a rudder and dried. The crude peptide is labeled on a 3 μ column / 10 x 2.14 cm / from Dyncmax C18 using a gradient from A: wodC / acetbnitayl / kwcs tπSlubibbutbO'y 95/5 / 0.2 and B: dito 20/80/0, 2 from 5% B to 80% B in 11 minutes, stream 20 ml, residence time 7.80 minutes. After drying the dreee, a colorless amorphous powder is obtained.

FAB-MS / M + H / + = 1327.9.

Example XXXV.

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

Using Fmoc-Ile-OH instead of Fnoc-Met-OH and without Fnoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 20%, 80% each in 10 minutes, time retention 3.25 minutes /.

FAB-MS / M + H / + = 1156.7.

Example XXXVI.

-Aca-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-IleZ using Fnoc-Aca-OH instead of Fmoc-lAla-OH and Fmou -niane-OH instead of FnocMet-OH and without Fmbu-kha-OH replaced the crude peptide is purified as described in Example 1, which is purified using the chromatography conditions described (20%, 80% B in 10 minutes, retention time 3.70 minutes). FaB-MS / M + H / + = 1198.8.

Example XXXVII.

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

Using Fnoc-Aund-OH instead of Fnoc-1 Ala-OH and Fmoc-Ile-OH instead of FnocMet-OH and without Fnoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is oueysecpa using the chromatography conditions described. 20% after 80% B in 10 minutes, retention time 5.55 minutes).

FAB _- MS / M + H / + = 1268.9.

Example XXXVIII. '«-Aca-Phe-Arg-P he-D-Ala-Gly-Arg-Ile-Asp-Arg-IleZ use n Fnoc-Aca-OH instead of Fnoc-l Ala-OH and Fnoc-Ils-OH instead of FnocMst-OH and without Fmoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is purified using the described uhromctbgaaSii conditions (20% for 80% B in 10 minutes, retention time 4.90 minutes).

FAB-MS / M + H / + = 1346.2.

168 456

Example XXXIX.

β) Ala-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile t

Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 20% for 80% B in 10 minutes. retention time 4.50 minutes /.

FAB-MS / M + H / + = 1304.0.

Example XL.

j- β Ala-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile-j

By additionally using Fmoc-Lys / BOC / -OH and Fmoc-Nle-OH instead of F ^ toc-Met-OH and without Fmoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatographic conditions described. (5% for 80% B in 11 minutes, retention time 6.10 minutes).

FAB-MS / M + H / + = 1275.0.

Example XLI.

r— ^β Al ^a- Fhe- Ar g ^-

Cr_

5er / Bzl / -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile

By additionally using Fmoc-Lys / BOC / -OH and Fmoc-Ser / Bzl / IOH instead of Fmoc-Cha-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH, a crude peptide is obtained as described in Example 1 and purified using the chromatography conditions described (5% 80% B in 10 minutes, retention time 6.20 minutes).

FAB-MS / M + H / + = 1305.0

Example XLII.

- A ca-Phe-Lys-Phe- D-Ala-Gly -Ar g-1 le-A sp-Arg-Ile-.

By using Fmoc-Aca-OH instead of Fmoc-βAla-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and FmocILys / BOC / IOH and without Fmoc-Cha-OH, a crude peptide is obtained as described in Example 1 and purified using the chromatography conditions described (5% after 80% B in 11 minutes, retention time 6.60 minutes).

FAB-MS / M + H / + = 1318.2

Example XLIH.

-Aca-Phe-Lys-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-Ilei --- 1

By additionally using Fmoc-Lys / BOC / -OH and Fmoc-Aca-OH instead of Fmoc-βAla-OH and F ^ toc-Ile-OH instead of FmocIMetIOH and without FmocIChaIOH, a crude peptide is obtained as described in Example 1, which is purified from using the chromatography conditions described (5% 80% B in 11 minutes, retention time 6.40 minutes).

FAB-MS / M + H / + = 1290.2.

Example XLIV.

«-Aca-Phe-Arg-Cha-D-Ala -Gly-Arg-Ile-Asp-Ar g-Ile-.

Using Fmoc-Aca-OH instead of FmocIβAla-OH and Fmoc-Ile-OH instead of FmocMet-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% by 80% B in 11 minutes , retention time 7.35 minutes /.

FAB-MS / M + H / + = 1352.2.

168 456

Example XLV.

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

Using Fmoc-Aca-OH instead of FmocjAla-OH and Fmoc-Ille-OH instead of Fmoc-Met-OH and Fmoc-D-Phe-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1. purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.35 minutes).

FAB-MS / M + H / + = 1346.2.

Example XLVI.

rA ca-C ha -Ar oP he-D-Ala-Gly-Arg-Ile- A sp-Arg-IleZ using Fmoc-Aca-OH instead of Fmoc-β Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met- OH is obtained as described in Example 1, a crude peptide which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 7.35 minutes).

FAB-MS / M + H / + = 1352.0. Example XLVH.

Ala-Phe-Arg-Cha-D-Ala-Gly-A.rg-Ile-Asp-Arg-1le Using Fmoc-Ile-OH instead of Fmoc-Met-OH is obtained as described in Example 1 a crude peptide which purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 5.90 minutes).

FAB-MS / M + H / + = 1309.5.

Example XLVIH.

Ala- / l-NDg / Phe-Arg-Phe-D-Ala-Gly-Arg-I le-Asp-Arg-Ile-i

By additionally using Fmoc- / 4-NO2 / Phe-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described. (5% for 80% B in 10 minutes, retention time 6.85 minutes).

FAB-MS / M + H / + = 1348.9.

Example XLIX.

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

By additionally using Fmoc-Lys / BOC / -OH and Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% after 80% B over 10 minutes, retention time 6.75 minutes /.

FAB-MS / M + H / + = 1281.9.

Example L.

p-Cl g-Αrg-Cha-D-A la-Gly-Arg-Ile-A sp-Arg-Ile-j

Using Fmoc-Clg-OH instead of FmocjAla-OH and Fmoc-Ile-OH instead

Fmoc-Met-OH and Fmoc-Phe-OH without Fmoc-Phe-OH were obtained as described in Example 1 a crude peptide which was purified using the chromatography conditions described (5% for 80% B in 11 minutes, retention time 7.35 minutes).

FAB-MS / M + H / + = 1259.8.

168 456

Example LI.

- β> βI ^ e / 4eNO2 / PhleAΓgeCha-DeAIaeGIyeAΓgeIIleAspeArgeIlle

Using Fmoca / 4aNO2 / Phe-OH instead of Fmoc-PhzaOH and Fmoc-I1z-OH instead of FmocaMztaOH, a crude peptide is obtained as described in example 1, which is purified using the chromatography conditions described / 5% by 80% B in 10 minutes , retention time 6.50 minutes /.

FAB-MS / M + H / + = 1C54.7.

Example LII.

p β eia-Tyr / Bzl / -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- |

Using FmocaTvr / Bz1 / -OH instead of Bmoc-Phe-OH and Bmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide is obtained as described in Example 1, which is purified under the chromatography conditions described / 5% by 80% B within 10 minutes, retention time 8.20 minutes /.

FAB-MS / M + H / + = 1415.9.

Example LIII.

- β) Ala-TyT-Arg-Cha-D-AAi-Gly-Aig-Ile-Asp-Arg-Ileii

Using Fmoc-Tyr / tBu / -OH instead of FmocaPhz-OH and Fmoc-I1z-OH instead of Fmoc-MetaOH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% by 80% B in within 10 minutes, retention time 6.45 minutes /.

FAB-MS / M + H / + = 1C 25.8.

Example LIV.

riThc-AAggCria --- Ala-Aly-AAggIle-Asp-AAggIle- | and _._____ i

Using Fmoc-Thc-OH instead of Bmoc-eAla-OH and FmocaI1eaOH instead of Bmoc-Met-OH and without Bmoc-Phe-OH a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% after 80% B within 10 minutes, retention time 6.45 minutes /.

FAB-MS / M + H / + = 1279.7.

Example LV.

t- P? Ala-Pas-CtT-Cha-D - Aa ~ Gly-Arg-iye-As - Arg-lle-j

By additionally using Bmoc-Ctr-OH and FmocaI1e-OH instead of Fmoc-Met-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5%, 80% B in 10 minutes, retention time 7 .00 minutes /.

FAB-MS / M + H / + = 1 Cl 10.6.

Example LVI.

_r Ta - P ae-Al □ -Cha --- AAa-Aly-AlggIle-lΞp-AAggIaeA

1_I____I

Using Fmoc-Thc-OH instead of Fmoc-eAla-OH and Fmoc-Ile-OH instead of

FmocaMzt-OH was obtained as described in Example 1, a crude peptide which was purified using the chromatography conditions described (5% B, 80% in 10 minutes, retention time 7.60 minutes).

FAB-MS / M + H / + = 1426.7.

1618456

Example LVII.

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

With the Zaltolation of Fmoc-Clg-OH instead of Fmou-βAla-OH and Fmou-Ile-OH instead of FmocMet-OH and without Fmoc-Phe-OH, a crude peptide is obtained as described in Example 1, which is exfoliated using the chromatographic conditions described / 5 % after 80% B in 10 minutes, retention time 8.90 minutes).

FAB-MS / M + H / + = 1406.7.

Example LVIII.

_| sAca - rg-Phe-D-Ala-GlyΓLys-Nle-AspΓArg-Ill-.

By additionally using Fmdc-Lys / BOC / -OH and Fmdu-Aca-OH instead of Fmoc-pAla-OH and Fmoc-Nle-OH instead of Fmou-Mat-0H and without Fmoc-Cha-OH, the crude a peptide that is purified from pasteurization of the described chromatography conditions (5% 80% B in 11 minutes, retention time 5.45 minutes).

FAB-MS / M + H / + = 1170.6. Example LIX.

.-Aca - rg-Ser / Bzl / -D-Ala-Gly-Lys-Nll-Asp-Arg-Ile- ₍

With the pasture of Fmdu-Aua-OH instead of Fmou-βAla-OH, Fmoc-Nla-OH instead of FmduMet-OH and Fmdc-Sar / Bzl / -OH instead of Fmdc-Cha-OH the crude peptide is obtained as described in Example 1 purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 5.70 minutes).

FAB-MS / M + H / + = 1200.5.

Example LX.

fsAca-PhlΓAr s-hlsDS-ASs-lly ^ l_ys-Nle-AΓs ^- Ils- _i

Using Zddatkdwd Fmou-Lys / BOC / -OH and Fmoc-Aua-OH instead of Fmou-βAla-OH and Fmdc-Ile-OH and Fmdu-Nle-OH instead of Fmdc-Mat-OH and without Fmou-Cha-OH and Fmoc- Asp (tBs) -OH was obtained as described in Example I, a crude peptide which was purified using the chromatography conditions described above (5% for 80% B in 11 minutes, retention time 7.10 minutes).

FAB-MS / M + H / + = 1089.5.

Example LXI.

Ala-Phe-Arg-Phe-DΓAlaΓGly-Lys-Nle-Arg-.Ile

Using Fmou-Lys / BOC / -OH and Fmdu-Nla-OH instead of Fmdc-Met-OH and without Fmoc-Cha-OH and Fmdu-Asp / tBu / -OH a crude peptide was obtained as described in Example 1. purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.90 minutes).

FAB-MS / M + H / + = 1160.6.

Example LXH.

| sAca-AΓg-Phl-D-Ala-GlyΓLys - le-Arg-IleΓ

Using Fmdc-Lys / BOC / -OH and Fmou-Aua-OH instead of Fmoc-PAla-OH and FmocNle-OH instead of Fmou-Mat-OH and without Fmdc-Cha-OH the crude peptide was obtained as described in Example 1, which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 5.95 minutes).

FAB-MS / M + H / + = 1055.7.

168 456

LXIB example.

A1a-AΓC-Phs_D-A1a_G1y_Lys_N1s-Arg_I1s_.

With the use of Fnou-Lys / BOk / -OH and Fnoc-Nle-OH instead of Fnoc-Mst-OH and without Fnoc-Posz-OH and Fnou-Asd / tBu / -OH a crude peptide is obtained as described in Example 1. purify using the chromatography conditions described (5% after 80% B for 11 minutes, standing time 5.90 minutes).

FAB-MS / M + H / + = 1013.6.

Example LXIV.

- _l Ala-Phe-Gly-Ser / Bzl / _D_AIa-Gly-i_ys-N1s-Asp-Arg_ϊ1s-, i k 1

Using Fmbu-Lys / BOk / -OH and Fmbc-Sei / Bzl / -OH and Fmoc-Nls-OH instead of Fnoc-Mst-OH and bsz Fnoc-Cha-OH was obtained as described in Example 1 a crude peptide which using the described chaomαtograSii conditions (5%, 80% B in 11 minutes, retention time 6.85 minutes).

FAB-MS / M + H / + = 1206.4.

Example LXV.

._Aca_Phs_GIy_P hs_D_A1a_G1y_Lys-t \ l1e_Asp ~ Arg_I1sy

Using Fnoc-Aca-OH instead of Fmbu-lAla-OH and Fnoc-Nle-OH instead of Fnoc-Mst-OH and Fnbu-Lys / BOC / -OH and without Fnoc-Cha-OH are prepared as described in example I crude peptide which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 7.40 minutes).

FAB-MS / M + H / + = 1248.5.

Example LXVI.

Ila-Gly-Ser / Bzl / _D_A1a_GIy_Lys_N1s_Asp_Arg_I1s_.

Using Fmbu-Lys / BOk / -OH and Fmoc-Ser / Bzl / -OH instead of Fmoc-Phs-OH and Fnoc-Nls-OH instead of Fnoc-Met-OH and without Fmbu-kha-OH is prepared as described in Example 1, a crude pspeptide which is purified using the described uhronatographic conditions (5% for 80% B in 11 minutes, retention time 5.80 minutes).

FAB-MS / M + H / + = 1059.4.

Example LXVII.

-Aca-Gly-Ser / Bzl / yDyA1a_G1y_Lys_NIs_Asp_Arg_I1s_

Using Fnoc-Aca-OH instead of Fmoc-lAla-OH, Fmoc-Ser / Bel / -OH instead of Fnoc-Cha- and Fnoc-Nls-OH instead of Fnoc-Met-OH, the raw pspeptide is obtained as described in Example 1, which was purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.20 minutes).

FAB-MS / M + H / + = 1101.5.

Example LXVIIL

- _ Ala-Ser / Bzl / -D-A1a_G1y_Lys_N1s_Asρ_Arg_I1s_

By using Fmbc-Sea / Bzl / -OH instead of Fnoc-Cha-OH and Fnoc-Ils-OH zanicst Fnoc-MetOH and additionally Fmoc-Lys / BOk / -OH a crude peptide is prepared as described in example I and purified from using the described chromatography conditions / 5%, 80% each

B within 11 minutes, retention time 6.05 minutes /.

FAB-MS / M + H / + = 1002.6.

168 456

Example LXIX.

.-Aca-Ser / Bzl / -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile-j

Using Fmoc-Aca-OH hinge Fkuc-βAlo-OH and Fwun-Ila-OH instead of Fmon-Mai-OH and Fmun-Sao / Bzl / -OH instead of Fmoc-Cha-OH and Fwoc-Lhs / BOC / -OH otoaywuja The method described in Example 1 was suoomh papthd,. Atóin was processed using the chromatography conditions described (5% B for 80% for 11 years, retention time 6.60 winui).

FAB-MS / M + H / + = 1044.5.

Example LXX.

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

1_____________!

With the sum of Fmoc-Btu-OH, the hinged Fwoc-eAla-OH and Fwun-Ile-OH, the hinged FmonMet-OH and without the Fkoc-Cha-OH, are prepared in the manner described in Example 1 suoumh paptyC, which is purified using the described chromatography conditions / 5 % after 80% B in 11 minutes, duration 5.35-11 ° C

FAB-MS / M + H / + = 1225.6.

Example LXXI.

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

With zaetusomaAiem Fwuc-D-Btu-OH, the hinge Fmon-βAla-OH and Fmon-Ila-OH instead of Fwoc-Met-OH, and without Fwuc-Cha-OH, the crude peptide is obtained as described in Example 1, which was raised using the described maounni chromatography (5% after 80% B over 11 winutes, retention time 5.15 minutes).

FAB-MS / M + H / + = 1225.6.

Example LXXII.

-Ala-Arg-Phe-D-Ala-Gly-Arg-Ile-Arg-Ilel_j__ ''

By replacing Fmoc-Ila-OH, the hinged Fmoc-Met-OH and without Fwon-Cha-OH and Fmoc-Asp / tBu / -OH are processed in the manner described in Example 1, raw pepi / d, which is purified from the stains described in the chronograph / 5% after 80% B over 11 winutes, retention time 6.15 minutes).

FAB-MS / M + H / + = 1041.5.

Example LXXIII.

-Aca-Arg-Phe-D-Ala-Gly-Arg-Iie-Arg-Iee-.

With the zostosomone Fwon-Aco-OH, the hinge Fmuc-βAlo-OH and Fmun-Ila-OH instead of Fmun-Met-OH and without Fmon-Cho-OH and Fmun-Asp / tBa / -OH are digested as described in Example 1 crude PaptnC, A different use was made of the described mooanni chromatography (5% by 80% B in 11 minutes, retention time 6.10 meau).

FAB-MS / M + H / + = 1083.9.

Example LXXIV.

- Aca-Phe-Ar g-Phie-D-Ala-Gly-Arg-Ile-Gly-Arg-IleZ using Fmoc-Ana-OH hinge Fmoc-eAlo-OH, Fmon-Ila-OH hinge Fwoc-Mat-OH and Fmoc-Gly-OH zamiasi Fwon-Zsρ / iBu / -OH and without Fwon-Cha-OH are obtained in the manner described in example I raw papthC, which is obtained using the described mΓIaani cryatogiafii / 5% at 80% B over 11 minutes, retention time 5.80 winut /.

FAB-MS / M + H / + = 1331.2.

168 456

Example LXXV.

-A ca-Phe-Arg-Tyr / OMie / -D-Ala-Gly-Arg-Ile-A sp-Arg-IleZ using Fmoc-Tyr / OMe / -OH and Fmoc-Aca-OH instead of Fmoc-βAla-OH and FmocIle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was obtained as described in Example 1, which was purified using the chromatography conditions described / 5%, 80% B in 11 minutes, retention time 6 , 85 minutes /.

FAB-MS / M + H / + = 1376.2.

Example LXXVI.

pAca-Phe-Arg-Phe-D-Ala-Gly-Arg-D-Ile-Asp-Arg-IleZ using Fmoc-Aca-OH instead of Fmoc-βAlaIOH and Fmoc-D-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described (5% B for 80% in 11 minutes, retention time 7.10 minutes).

FAB-MS / M + H / + = 1346.2.

Example LXXVII.

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

Using Fmoc-DIAs- / tBu / IOH instead of Fmoc-Asp / tBu / -OH, Fmoc-Aca-OH instead of Fmoc-βAlaIOH and Fmoc-IleIOH instead of Fmoc-Met-OH and without Fmoc-Cha-OH the crude peptide described in Example 1, which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.60 minutes).

FAB-MS / M + H / + = 1346.0.

Example LXXVIII.

-Aca-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-IleZ using Fmoc-D-Ar- / Mtr / IOH and Fmoc-Aca-OH instead of Fmoc-βAlaIOH and Fmoc- Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5%, 80% B in 11 minutes, retention time 6. 65 minutes /.

FAB-MS / M + H / + = 1346.0.

Example LXXIX.

-Aca-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-IleZ using Fmoc-D-Phe-OH and Fmoc-Aca-OH instead of Fmoc-βAlaIOH and Fmoc-fleIOH instead of Fmoc -Met-OH and without Fmoc-Cha-OH was obtained as described in Example 1 a crude peptide which was purified using the chromatography conditions described (5% B, 80% in 11 minutes, retention time 6.55 minutes).

FAB-MS / M + H / + = 1346.0.

Example LXXX.

-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-IleZ using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-Aca-OH is obtained in as described in Example 1, a crude peptide which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.55 minutes).

FAB-MS / M + H / + = 1232.5.

Example LXXXXI.

- βAlaτPhl-Argτphl-DτAlaτGlyτArgτIleτAspτD-ArgτIleτ I __: _______________ I

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

FAB-MS / M + H / + = 1303.7.

Example LXXXII - Q. Alaτphl-DτAroτPheτDτAlaτGlyτ & ro-IllτAspτDτArgτIllτ

L -11 ------ i

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

FAB-MS / M + H / + = 1346.0.

Example LXXXIII.

.τArgτPhlτDτAlaτGly-ArgτIll-A sp — Arg — Ile—

Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-β Ala-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% after 80 % B on 11 minutes, retention time 5.45 minutes /.

FAB-MS / M + H / + = 1085.5.

Example LXXXIV.

- β Ala-Phl-D-ArgτPhlτD-Ala-Gly-Arg-IllτA sg-Arg-Ile—

Using Fmoc-D-Arg / Mtr / -OH instead of Fmoc-Arg / Mtr / -OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH the crude peptide was obtained as described in Example 1 which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.40 minutes).

FAB-MS / M + H / + = 1303.7.

Example LXXXV.

- β Ala-Phe — Arg — ChaT, Azt-Gly-Arg-Ile-Asp - Arg-IleZ using Fmoc-Azt-OH instead of Fmoc-D-Ala-OH and Fmoc-Ile-OH instead of FmocMet-OH is obtained as described in Example 1, a crude peptide which is purified using the chromatography conditions described (5%, 80% B in 10 minutes, retention time 7.20 minutes). '

FAB-MS / M + H / + = 1321.7.

Example LXXXVI.

T Aa Ala — Arg-Cha-DTAla-Gly-Arg-IleTAspTArgT Ile—

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

FAB-MS / M + H / + = 1162.5.

168 456

Example LXXXVII.

-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Ar - ie - j

Using Fnoc-Ile-OH instead of Fnoc-Met-OH and bsz Fnoc-1Ala-OH was obtained as described in Example 1 of a crude peptide which was purified using the described conditions chrbnatbgrcSii / 5% 80% B in 10 minutes. retention time 6.10 minutes /.

FAB-MS / M + H / + = 1091.5.

Example LXXXVIH.

-P he-Arg-Cha-D-Als-Gly-Arg-Ile-Asp-Arg-IleZ using Fnoc-Ile-OH instead of Fmoc-Mst-OH and without Fnoc-lAla-OH are prepared as described in Example 1 crude peptide which is purified using the chromatography conditions described (5%, 80% B in 10 minutes, retention time 8.25 minutes).

FAB-MS / M + H / + = 1238.8.

Example LXXXIX.

H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile Pspeptide synthesis is carried out on the Advanced ChenTech ACT200 peptide synthesizer using Fnoc-strategy using a modified control program. A 50 ml shake reactor is charged with 1 g of 2-netoxybeneylbwsgb ester resin from Bachem, Switzerland. saturated 0.5 mmol of Fnoc-ieblsuine. The following amino acid derivatives are used: Fmou-Aag / Mtr / -OH, Fnou-Asp / tBu / -OH, Fnoc-Nle-OH, Fmou-Lys / BOk / -OH, Fnoc-Gly-OH, Fnoc-D-Ala -OH, Fnoc-Phe-OH, and BOk-Lys / Fmoc / -OH. Coupling is carried out using 3 equivalents of Fmoc-anino acid, 1-h-hydroxybenzotriaeol and dicyclohexslokaabbdiimide each (40 ninut coupling time). After presetting the TNBS tsst, in the case of incomplete Tcstations, the coupling is repeated using these suitable reagents and excesses. In the case of complete acylation, the next synthesis cycle is recognized. The deprotection of Fnoc is carried out each time with 20% piperidine in DMF (once 3 minutes, once 15 minutes).

Between reactions, the resin is washed 10 times each time with DMF. After building the linear sequence B0k-Lys-Aag / Mtr / -Phe-D-Alα-Gly-Lys / BOk / -Nls-Asd / tBu / Arg / Mtr / -Ile- on the polymer carrier, the resin is washed thoroughly with dichloromethane and then treated with 5 times each time with 20 ml of a 1% solution of taiSluorobctic acid and in dichlbrometanis for a maximum of 10 minutes at room temperature / until the resin intensely colored /. The solutions were combined and concentrated in vacuo. The residue is triturated with ether, the ether is decanted, the peptide is dried in a stream of nitrogen and taken up in 130 nl of DMF, the pH value is adjusted to about 8.5 with Tmine triethica, the solution is cooled to -20 ° C, and 0.2 g / 0.75 mnoli / diSenyloSbsfbaylbaesdku. The mixture is left for 48 hours at -20 ° C and 48 hours at temperature. 4 ° C. The pH value is kept at 8.5 with triethylanine. The DMF is then removed in vacuo, the residue is triturated twice with ether, the ether is decanted and the residue is dried under nitrogen gas. The side chain protecting groups are determined with trifluorooutbwsgb (αnieol (90/10) acid for 24 hours at room temperature. The solution is concentrated in vacuo, the residue is stripped from the etsren and dried. The crude pspeptide is purified on a 3 μ column / 10 x 2.14 cn / by Dynanax C18 using a gradient from A: wbdy / auetbnitrile / triSluorobctbwsgo acid 95/5 / 0.2 and B: dito 20/80 / 0.2 from 5 % to 80% B in 11 minutes, stream 20 nL, retention time 5.25 minutes. After freeze drying, an amorphous colorless powder is obtained.

FAB-MS / M + H / + = 1186.0.

168 456

XM Example.

Z-Lys-Arg-Phe-D-Ala-Gly-Lys-i \ Jle-Asp-Arg-Il-- |

Using Z-Lys / Fmoc / -OH instead of BOCILys / Fmoc / -OH, a crude peptide was obtained as described in Example 1, which was purified using the chromatography conditions described / 5%, 80% B in 11 minutes, retention time 6 , 60 minutes /.

FAB-MS / M + H / + = 1320.0

XMI example.

Z-Lys-Arg-Ser / Bzl / -D-Ala-Gly-Lys-Nlp-Asp-Arg-Jle Z using Z-Lys / Fmoc / -OH instead of BOC-Lys / Fmoc / -OH and Fmoc-Ser / Bzl (OH) instead of Fmoc-Phe-OH, a crude peptide was obtained as described in Example 1, which was purified using the chromatography conditions described (5% _: 80% B in 11 minutes, retention time 6.95 minutes).

FAB-MS / M + H / + = 1350.0.

Example XMII.

Bz-Lys-Arg-P he-D-Ala-Gly-Lys-Nle-A sp-Arg-IleZ using BzILys / Fmoc / IOH instead of BOC.-Lys / Fmoc / -OH is prepared as described in Example 1 crude a peptide which is purified using the chromatography conditions described / 5% 80% B in 11 minutes; retention time 6.00 minutes /.

FAB-MS / M + H / + = 1290.0.

XMIH example.

Z-Ly s-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile Z using Z-Lys / Fmoc / -OH instead of BOC-Lys / Fmoc / -OH and without Fmoc-Nle-OH and The FmocILys (BOC / IOH) was obtained as a crude peptide as described in Example 1, which was purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 6.65 minutes).

FAB-MS / M + H / + = 1348.0.

Example XMIV.

H-Lys-Arg-Cha-D-Ala-Gly-Ara-Ile-Asp-Arg-IleZ using Fmoc-Cha-OH instead of Fmoc-PheIOH and Fmoc-Ile-OH instead of Fm ^ c-Nle-OH and without Fmoc -Lys (BOC) -OH was obtained as described in Example 1 a crude peptide which was purified using the chromatography conditions described (5% BOC, 80% in 11 minutes, retention time 6.00 minutes).

FAB-MS / M + H / + = 1219.7.

Example XMV.

Z-LysL

Using Z-Lys / Fmoc / -OH instead of BOC-Lys / Fmoc / -OH, Fmoc-Cha-OH instead of

Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys / BOC / -OH a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% after 80 % B on 11 minutes, retention time 6.35 minutes /.

FAB-MS / M + H / + = 1353.7.

168 456

Example XMVI.

Menoc-Lys-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ilei I i- ------- With Me-oc-Lys / Fino ^ -OH instead of BOC-Lvs / Fmoc / -OH and ^ α-IIz-OH instead of Fmoc-N1z-OH and without Fmoc-Lys / BOC / -OH a crude peptide was obtained as described in Example 1, which was purified using the chromatography conditions described / 5% after 80 % B on 11 minutes, retention time 8.20 minutes /.

FAB-MS / M + H / + = 1C95.8.

Example XMVII.

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

Using Menoc-Lys / Fmoc / -OH instead of BOCaLvs / Fmoc / aOH, Fmoc-Cha-OH instead of Bmoc-Phe-OH and FmocaI1eaOH instead of ^ oc-Nle-OH and without FmocaLys / BOC / -OH are obtained as described in Example 1, the crude peptide which is purified using the chromatography conditions described (20%, 80% B in 11 minutes, retention time 7.00 minutes).

FAB-MS / M + H / + = 1402.0

Example XMVlll.

H-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile! _____ L

Using FmocaI1e-OH instead of Bmoc-Nle-OH and without Fmoc-ChaaOH instead of Fmoc-Phe-OH, a crude peptide is obtained as described in Example 1, which is purified using the chromatography conditions described / 5% by 80% B for 11 minutes, retention time 6.40 minutes /.

FAB-MS / M + H / + = 1191.8.

XMIX example.

Z-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-IleZ using ZaLys / Fmoc / -OH instead of BOCaLys / Fmoc / -OH and FmocaI1z-OH instead of Fmoc-Nle-OH is obtained in as described in Example 1, a crude peptide which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 7.75 minutes).

FAB-MS / M + H / + = 1C26.0.

The example of M.

Z-Lys-P.he-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-IleZ using Z-Lvs / Fmoc / aOH 'instead of BOC-Lys / Fmoc / aOH and Bmoc-Ile-OH instead of hmoc -Nle-OH is obtained as described in Example 1, a crude peptide which is purified using the chromatography conditions described (5%, 80% B in 11 minutes, retention time 8.40 minutes).

FAB-MS / M + H / + = 1CC 9.0.

Example of MI.

/ 4-NO? / Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-.

ι I

Using / 4-NO2Z-Lys / Fmoc / -OH instead of BOC-Lvs / Fmoc / -OH, FmocaI1e-OH instead of Fmoc-N1z-OH and Fmoc-Cha-OH instead of FmocaPhz-ΌH is obtained as described in the example And the crude peptide which is purified using the chromatography conditions described (5%, 80% B in minutes, retention time 8.45 minutes).

FAB-MS / M + H / + = 1C98.9.

168 456

Mia's example.

Z-Lys-OΓa-Zha-Z-ΆZa-Gly-Azg-Ila-Zsp-Azg-Ilei I

------:

From zaetoeomoAtamZ-Lhs / Fwoc / -OHzamtostBOC-Lhs / Fwuc / -OH, Fmon-Cąo-OH żowiaei Fmon-Phe-OH and Fmun-Ila-OH with Fwuc-Nle-OH and dodotnuwo Fmun-Orn / BOC / -OH This is the same as described in progeny I a crude peptide which was learned using the mΓouAnt nhruvotogophy described (5% by 80% B in 11 minutes, retention time 7.80 wiAai).

FAB-MS / M + H / + = 1311.8.

Example MIII.

H-LLh-Azg-Ser / Bzl / -Z-Zlo-lly-Lhe-Nla-Zep-Z: rg-Ila- | i___I

From żostusumoniam Fmon-Sao / Bal / -OH instead of Fwon-Phe-OH, a crude peptide was obtained as described in Catate I, which was processed using a? 1? 0.0? chromatography (5% after 80% B over 11 vinutes, with a retention of 5.55 winui).

FAB-MS / M + H / + = 1216.0.

MIV example.

Bz -1- y s-Z r g - P h e-D -i Zl- G ly - L L / s -JNe - A sp - A zr -1 lei --- i

From zoeausowoAtam Ba-Lye / Fmun / -OH, BOC-Lys / Fmuc / -OH, the raw peptide is digested in the manner described in the film I, the raw peptide is purified by sausage, by the written chromatography conditions / 5% by 80% B in the week 11 meats, time retention 6.40 minu /.

FAB-MS / M + H / + = 1290.0

Example MV.

Bz-Ly s-Azg-5er / Bzl / -Z-Zlo-lly-Lys-Naa-Z ep-ZΓg-Iae-l

With the use of Ba-Lys / Fmoc / -OH instead of BOC-Lys / Fwun / -OH and Fmuc-Ser / Bzł / -OH instead of Fmun-Pha-OH the crude peptide is identified in the manner described in the method I, the crude peptide is chromatography mooanki (5% after 80% B in 11 minutes, retention time 6.35 minutes).

FAB-MS / M + H / + = 1319.7.

MVI example.

Bz-D-t..Ly-Azr-SearBBZ / -Z-Zla-lly-LLh-Nne-Azp-Azr-ΐlai ---- 1

From aoethosomoniam Bz-D-Lys / Fmun / -OH, BOC-Lhs / Fmoc / -OH and Fmon-Seo / Bżl / -OH, the Fmon-Phe-OH saroma is obtained as described in Example 1 of the paptnC saroma. I used the described πι ^ αΑ chromatography / 5% after 80% B in 11 minutes, retention time 6.70 minutes /.

FZB-MS / M + H / + = 1319.8.

Example MVII.

Tos-Lys-Azg-Phe-ZzAZao-lanAzg-Ile-A se-Azz-ϊlaZ zosaoeuwoniam Wus-Lye / Fmon / -OH instead of BOC-Lys / Fmon / -OH and Fmon-Ile-OH while Fmuc-Nla-OH The crude peptide which is purified by baking wake chromatography (5% after 80% B in 11 minutes, oet time 6.90 minutes) is identified by the method of preparation.

FAB-MS / M + H / + = 1367.7.

168 456

Example MVIII.

H-Ly s-Ar g — P he-klg-Arg-I ls-A sp-Ar g-1lei __________!

Using Fmou-Clg-OH instead of rmoc-Gly-OH and instead of Fmdc-D-Ala-OH and Fmoc-Ile-OH instead of Fmdu-Nłe-OH the crude peptide is obtained as described in Example 1 and purified using the described chromatography conditions (5%, 80% B in 11 minutes, retention time 4.85 minutes).

FAB-MS / M + H / + = 1253.8.

Example MIX.

Z-Lys-Arg-Phe-klg-Arg-He-Asp-Arg-Ile Z using Z-Lys / MoU-OH instead of BOC-Lys / Fmdu / -OH, Fmoc-Clg-OH instead of Fmdu-Gly-OH and Fmdu -D-Ala-OH and Fmdu-Ile-OH instead of Fmoc-Nla-OH and without Fmoc-Lys / BOC / OH a crude peptide is obtained as described in Example 1 which is purified using the chromatography conditions described / 5% after 80% B in 11 minutes, retention time 6.85 minutes /.

FAB-MS / M + H / + = 1387.8.

MX example.

Z-Lys-Arg-kha-clo-Arg-Ile-Asp-Arg-IleZ pastosdwaniam Z-Lys / Fmdu / -OH instead of BOC-Lys / Fmdc / -OH, Fmdu-Cha-OH instead of Fmou-Phe-OH and Fmou-Ile-0H instead of Fmdc-Nła-OH and Fmdc-Clg-OH instead of Fmdu-Gły-OH and instead of Fmdu-D-Ała-OH and without Fmdc-Lys / BOC / -OH is prepared as described in Example 1 crude peptide which was extracted using the described chromatography conditions (5% 80% B in 11 minutes, retention time 8.70 minutes).

FAB-MS / M + H / + = 1394.0.

MXI example.

Z-Ly ε-ΑΓρ-ΟΚΒ-Ο-ΟΟο-Α-ς-Ι! ^ - sp-Ag-IleZpastosooanίemZ-Lys / Fms) u / -0HpamiastB0C-Lyss / Frkdc / ~ 0H, Fmdu-Cha-OH instead Fmoc-Phe-OH, Fmoc-ClgiOH instead of Fmoc-GlyiOH and Fmou-D-AlaΙOH and Fmoc-Ile-OH instead of FmdUΙNlaΙOH and without Fmdu-Lys / BOC / -OH, the crude peptide that exfoliates using the chromatography conditions described (5% 80% B in 10 minutes, retention time 9.80 minutes).

FAB-MS / M + H / + = 1393.9

MXII example.

HQ ^ pAg-Ch ^ -D-Α-l-Gly-Ag-Ila-Asp-Al --— IleZ substituting BOCiDap / Fmoc / -OH instead of BOC-Lys / Fmoc / iOH, FmouΙIle-OH instead of Fmoc-NleiOH and without Fmdu-Lys (BOC) -OH, a crude peptide is obtained as described in Example 1, which is purified using the described uhromatofry conditions (5% for 80% B in 10 minutes, retention time 6.85 minutes).

FAB-MS / M + H / + = 1177.5

Example MXIII.

Z-Dap-Ag-kha-D-AAa-Gly-Arg-Ile-A sp-Arg-Ile Z using ZΙDap / Fmou / -OH instead of BOCΙLvs / Fmou / ΙOH, Fmou-Cha-OH instead of FmocΙPaeΙOH and Fmou-Ila- 0H instead of Fmdu-Nle-OH and Fmdc-Lys / BOC / ΙOH, the crude peptide was obtained as described in Example 1, which was dcpvscp using the described cardmataphy conditions / 5%, 80% B in 10 minutes, retention time 8 ,10 minutes/.

FAB-MS / M + H / + = 1311.6

168 456

Similarly prepared / 4-NG2 / Z-Lys-Arg-Cha-D-Ala-Gly-Arg-f'let-A sp-Arg-Ile ^ά 1 j

Purification using the chromatography conditions described (10% after 90% B in 10 minutes, retention time 7.4 minutes)

FAB-MS / M + H / + = 1417.0.

/ 4-NO2 / Z-Lys-Orn-Cha-D-Ala-Gly-Ar g-Ile-Asp-Arg-11e Purification using the chromatography conditions described / 10% B for 90% in 10 minutes, retention time 7, 8 minutes /.

FAB-MS / M + H / + = 1356.6.

MXIV example.

Z-Pyridylacetyl-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile Peptide synthesis is carried out on the ACT200 peptide synthesizer from Advanced ChemTech using Fmoc-strategy using a modified control program. A 50 ml shake reactor is charged with 1 g of 2-methoxybesyl ester resin from Bachem, Switzerland, saturated with 0.5 mmol of Fmoc-isoleucine. The following amino acid derivatives are used: Fmoc-Arg / Mtr / -OH, Fmoc-Asp / tBu / -OH, Fmoc-Ile-OH, Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc-Cha-OH and 2-pyridylacetyl-Lys (Fmoc) -OH. The coupling is carried out using 3 equivalents each of Fmoc-amino acid, 1-hydroxybenzotnase and dicyclohexylcarbodiimide (coupling time 40 minutes). Following the TNBS test, in the case of incomplete acylation, the coupling is repeated using the same reagents and excesses. In the case of complete acylation, the next synthesis cycle begins. The cleavage of the Fmoc protecting groups is carried out each time with 20% piperidine in DMF (once 3 minutes, once 15 minutes).

The resin is washed 10 times with DMF between the reactions. After building a linear sequence of 2-pyridylacetyl-Lys-Arg / Mtr / -Cha-D-Ała-Gly-Arg / Mtr / -IleAsp / tBu / -Arg / Mtr / -Ile- on the polymeric carrier, the resin is washed thoroughly with dichloromethane and then treated with 5 times each time with 20 ml of a 1% solution of trifluoroacetic acid in dichloromethane for a maximum of 10 minutes at room temperature (until intense lilac color of the resin occurs). The solutions are combined and concentrated in vacuo. The residue is triturated with ether, the ether is decanted, the peptide is dried under a stream of nitrogen and dissolved in 130 ml of DMF, the pH is adjusted to about 8.5 with Methylamine, the solution is cooled to -20 ° C and 0.2 g is added. (0.75 mmol) diphenylphosphorylazide. The mixture is left for 48 hours at -20 ° C and for 48 hours at 4 ° C. The pH value is kept at 8.5 with methylamine. Then the DMF is 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 side chain protecting groups are cleaved with trifluoroacetic acid (anisole (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 on a 3μ column / 10 x 2.14 cm / through Dynamax C18 using a gradient with A: water / acetonitrile / trifluoroacetic acid 95/5 / 0.2 and B: dito 20/80 / 0.2 from 10 % B to 90% B in 11 minutes, stream 10 mL / minute, retention time 8.2 minutes. After freeze drying, an amorphous colorless powder is obtained.

FAB-MS / M + H / + = 1338.6.

Examples MXV to MXXIV.

X-Lys-Ara-Cha-D-Ala-Gly-Aro-Ile-Asp-Arg-Ile60

168 456

Using X-Lss / Fmou / -OH instead of 2-diaydylacetyl Lys / Fmoc / -OH, a crude pspeptide was prepared as described in Example 1, which was purified using the chromatography conditions described / 10% for 90% B in 11 minutes. retention time see the following tabslc /.

Table

Example no X retention kpas / minutes / FAB-MS / M + H / 1 2 3 4 MXIV CTT 8.2 1338.6 MXV OO 'χ / b ₀ 9.5 1393.7 MXVI σΧγ 0 9.9 1402.6 MXVII (X. c 6.7 1325.8 MXVIII 8.3 1382.8 MXIX ^r 0 8.7 1385.8 MXX ^Gr □ 7.8 1415.7 /1417.7/ 1Br MXXI X ” ² H 0 7.6 1398.8 MXXII ^cl ~ © - ° © <0 8.0 1388

168 456 the table continues

1 2 3 4 MXXIII C. 8.1 1404 MXXIV 0 7.5 1422

(1): Deviation from Example 1 purification: 10% B to 90% in 10 minutes, flow 10 ml / minute.

Gel / for percutaneous use, especially in combination with iontophoresis /

10% active ingredient of the general formula I in citrate buffer pH 4.1 (see composition below)

0.25% agarose

Composition of citrate buffer pH 4.1 10.5 g citric acid monohydrate 100.0 ml sodium hydroxide solution 1 mol / liter to 500.0 ml distilled water j> - solution I 100.0 ml hydrochloric acid 0.1 mol / liter 1 to 250.0 ml solution I. / solution II

The above solution is heated to about 60 ° C with stirring and allowed to cool to room temperature after all the agarose particles have dissolved.

Injection solution:

10.5 g NaH2PO4.2H2O]

95.5 g of Na2HPO4. 12H2O> buffer pH 7.4

22.0 g of NaCl J to 5.000 ml of distilled water

This buffer solution is kept in an autoclave for 30 minutes at 121 ° C and 1 atmosphere gauge pressure.

1.5 g of active ingredient of the formula I are introduced into this solution, and the entire solution is sterile filtered.

In these formulation examples, for example, a compound can be used

M-NOa / Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-;

1_I or one of the other compounds outlined above.

168 456

Claims (20)

1. The method of producing cyclopeptides of the general formula I with ANP agonist activity, -An-Bn-Cn-Dn-En-Fπ-Gn-Hn-In-Kn- _{/ T} , where the sequence of Bn to Kn is the sequence of hANP amino acid residues Arg / 27 / -Phe / 8 / -Gly / 9 / -Gly / 10 / -Arg / 11 / -Met / 12 / -Asp / 13 / -Arg / 14 / -Ile / l 5 / - or Bn is an α-amino acid residue with one or two side chains, one or both of the side chains of which contains one, two, three or four basic groups, Cn is a cc-amino acid residue with one or two optionally containing -O-, -S- or -C / O / O-alkyl side chains, the side chains or one of both side chains having one or two radicals, where each radical is a cycloalkyl group of 3 to 10 carbon atoms, phenyl, naphthyl, substituted (e.g. by hydroxy, phenyl (C 1 -C 4) -alkyloxy, (C 1 -C 3 -alkoxy, NO 2), phenyl or 5- or a 6-membered aromatic heterocyclic group in which 2 members are N, or one member is N, one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl, Dn and En, independently of each other, each represent Gly or an α-amino acid residue which mimics the spatial structure of the native amino acid Gly, or Dn and En together represent an ω-amino acid residue -NH- / CH2 / 2-1 ι-CO-, or a peptide form (templat), Fn is an α-amino acid residue with one or two side chains, the side chains or one of both side chains having one, two, three or four basic groups, Gn is an α-amino acid residue with one or two lipophilic side chains, Hn is Gly or an α-amino acid residue which does not contain any functional group in the side or side chains or has a functional group -COOH or CONH2, In represents an α, -amino acid residue with one or two side chains, one or both side chains containing one, two, three or four basic groups, Kn represents an α-amino acid residue with one or two lipophilic side chains, and An denotes a spacer group that connects Bn with Kn and influences the spatial structure of the respective molecule so that the cyclopeptides bind to ANP receptors, whereby An means a) the group -A1-A2-A3- where Aj is Gly or an α-amino acid residue where the side chain or chains do not contain any functional group, A2 is a covalent bond or a ω-amino acid residue of the formula -NH- / CH2 / 11-CO- II where n is an integer from 1 to 11, A3 is a cc-amino acid residue with one or two optionally including -O-, -S- or -C / 0 / O alkyl side chains, one or both side chains containing one or two radicals, each radical being a cycloalkyl group of 3 to 10 carbon atoms, phenyl, naphthyl, substituted (e.g. by hydroxyl, phenyl (C 1 -C 4) alkoxy (C 1 -C 4) alkoxy, NO ') phenyl or 5,168,456 or 6-membered aromatic heterocyclic group where 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, fuiyl, pyrrolyl, imidazolyl, pyrazolyl, pnydyl, pnazidyl, pyrimidyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl, or b) the group -A4-A5- where A4 represents the peptide form (templat) or the ω-amino acid residue of the formula -NH- / CH ₂ / "- CO- II where n is an integer from 1 to 11 A5 represents a covalent bond or an α-amino acid residue with one or two optionally containing -O-, -S- or -C / O / O-alkyl side chains, one or both side chains containing a radical or two radicals, each the radical is a cycloalkyl group with 3 to 10 carbon atoms, a phenyl group, a naphthyl group, substituted (e.g. by a hydroxyl group, phenyl (C1-C4) -alkoxy, (C1-C4) -alkoxy, NO ') phenyl or 5- or Octa-membered aromatic heterocyclic group in which 2 members are N or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazidyl, pyrimidyl, pyridazilyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholyl or c) an amino acid residue of formula III -NH- (CH ₂ ) _m -CH (R) -CO- ΠΙ where m is an integer from 1 to 11 and R is ΝΗΧ, OX, SX, ΝΧΥ, -NH / H / -C / O / -CH ^L ₂ -X, -N / H / C / O / CH ₂ -ox ¹ N / H / C / O / X ', N / H / C / O / -CH = CH -X ¹ or Ν / ΗΛΟΛΟ-Ο ^ -Χ ¹ , where X represents a hydrogen atom, an unsubstituted or substituted benzoyl group, an unsubstituted or substituted cyclohexyloxycarbonyl group, an unsubstituted or substituted benzyloxycarbonyl group, a 2-, 3- or 4-pyridylmethyloxycarbonyl group, or a tosyl group, Y is a C1 to C14 alkyl group or an aryl (C1-C14) alkyl group, and X ^I represents / a / phenyl, / β / through 1, 2 or 3 substituents (halogen, trifluoromethyl or nitro substituents) substituted phenyl, / y / naphthyl, / o / benzo / b / thienyl, / e / pyridyl or / rj / pyrazinyl and their pharmaceutically acceptable salts, characterized by building the following linear sequence of peptides An-Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn-OH from the appropriate amino acids AnBnOH, CnOH, DnOH, EnOH, FnOH, GnOH, HnOH, InOH and KnOH each time contain a protective group known in chemistry of peptides by coupling method and then cyclizing the linear peptide and optionally converting to the corresponding salt. 2. The method according to p. The method of claim 1, wherein the amino acid AnBnOH is used, wherein An in the portion closest to Bn contains an aromatic or cycloaliphatic group. 3. The method according to p. A method according to claim 1 or 2, characterized in that the amino acids AnBnOH, CEnOH, EnOH, FnOH, GnOH, HnOH, InOH and KnOH are used in the form of L. 4. The method according to p. The method of claim 1, wherein the BnOH is an α-amino acid with one or 2 side chains, one or both of which contain one, two, three or four basic groups; CnOH is an α-amino acid with one or two optionally containing -O-, -S- or -C / O / O-alkyl side chains, the side chains or one of the two side chains having one group or two groups, each denoting a cycloalkyl group with 3 to 10 carbon atoms, a phenyl, naphthyl radical, substituted (e.g. by a hydroxyl group, phenyl (C 1 -C 4) -alkyloxy, (C 1 -C 4) -alkoxy, NO ₂ / phenyl or 5- or 6 - a membered aromatic heterocyclic group in which 2 members are N, or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl , pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl; 168 456 as DnOH and EnOH independently of each other are used Gly or α-amino acid that reproduces the spatial structure of the natural amino acid Gly, or Dn and En together constitute a residue of the ".-Amino acid -NH- / CH2 / 2-11-CO- or the form peptide (templat); Pn / FU Oho sla c; . α ^ -InK AkPi WonauAbOk0 ł-ł VtArT // - »łn J CŁTW A 11V_ZA A OLUÓUJU VA Ciii Hit Vi \ * v UO w J VzVJ.11 j lii ivx vz vj * »wu runvuvuuvii zr \ jzzZLŁj vn, z xwv / xj vii one or both contain one, two, three or four basic groups ; GnOH is an α-amino acid with one or two lipophilic side chains; HnOH is Gly or an α-amino acid which has no functional group in one or more side chains or has -COOH or -CONH 2 as a functional group; as InOH, an α-amino acid with one or 2 side chains is used, one or both of which contain one, two, three or four basic groups; as KnOH, an α-amino acid with one or two lipophilic side chains is used. 5. The method according to p. 4. The process of claim 4, wherein the BnOH, FnOH and InOH are independently of each other used an α-amino acid with a side chain that contains one or two basic groups; α-cmino wcs with a side chain is used as CnOH; as DnOH and EnOH independently of each other Gly or α-amino acid is used, which recreates the spatial structure of the natural amino acid Gly, or Dn and En together constitute an ω-amino acid residue -NH-CH2 / 2-5-CO- or peptide form (templat); as GnOH and KnOH, independently of each other, an α-amino acid with a lipophilic side chain is used, the side chain being a (C 1 -C 6) -alkyl radical which may also contain one or two -S- or -O- atoms in the chain; as HnOH. Gly or a "amino acid is used, wherein the side chain is (C 1 -C 6 alkyl, phenyl) (C 1 -C 6 -alkyl, H 2 N -CO- / CH 2 / 1-4 or HOOC- / CH 2 / 1-4-). 6. The method according to p. 5, characterized in that Arg, D-Arg, Lys, D-Lys, Orn, D-Orn, Homo-Arg, D-Homo-Arg, Dap, D-Dap are used independently as BnOH and FnOH and InOH or 4-amino-Phe, preferably Arg, D-Arg, Lys, D-Lys or Orn; CnOH is Phe, D-Phe, 4-NO2-Phe, Cha, D-Cha, Ser / Bzl /, D-Ser / Bzl /, Tyr, D-Tyr, Tyr / Bzl /, D-Tyr / Bzl /, Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or D-Glu (Bzl), preferably Phe, Cha, Tyr , Nal, Tyr (Bzl) or (4-NO2) -Phe; as DnOH and EnOH are used independently of each other Ala, Gly, Pro, Ser, Asn, Lys, Asp or Thr or their D-forms, preferably Dn is D-Ala, Gly, Pro, D-Pro, Ser or D-Ser; Gly, Asp or Asn is used as EnOH; or Dn and En taken together are an ω-amino acid residue of formula -NH- / CH2 / 2-5-CO- or a peptide form (templat), preferably Btu, Clg, Thc or Trc or their D-forms, especially D-Btu; as GnOH and KnOH are used independently of each other Ile, D-Ile, Met, D-Met, Nle, D-Nle, Leu, D-Leu, Val, or D-Val, preferably Ile, Met, Nle or Leu; HOOC- (CH2 / 1-4-CH / NH- / - COOH, their D, Gly, Ala, D-Ala, Asn, D-Asn, Phe or D-Phe forms, preferably Asp, Glu or Gly. 7. The method according to p. The method of claim 1 or 2, wherein the amino acid AnBnOH is used in which An is a) group - Ai - A2 - A3-, in which Ai is Gly or an α-amino acid residue in which one or more side chains do not contain any functional group; A2 is a covalent bond or a ω-amino acid residue of the formula -NH- (CH2 / 11 -CO- / Π / wherein n is an integer from 1 to 11; A3 is an α-amino acid residue with one or two optionally containing -O-, -S or -C / O / O-alkyl side chains, the side chains or one of the two side chains containing one group or two groups, each group being represents a cycloalkyl group of 3 to 10 carbon atoms, a phenyl, naphthyl radical, substituted (e.g. by a hydroxyl group, phenyl / C 1 -C 6 -alkyloxy, / C 1 -C 6 -alkoxy, NO ') phenyl or 5- or 6-membered aromatic heterocyclic group in which 2 members are N, or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl; or b) group - A4 - As in which A4 represents a peptide form (template) or a ω-amino acid residue of the formula -NH- (CH ₂ / _n -CO- (11) in which n is an integer from 1 to 11; As is a covalent bond or an α-amino acid residue with one or two optionally containing -O-, -S- or -C / O / O-alkyl side chains, the side chains or one of the two side chains containing one group or two groups , where each group represents a cycloalkyl group with 3 to 10 carbon atoms, a phenyl, naphthyl radical, substituted (e.g. by a hydroxyl group, phenyl (C 1 -C 4) alkyloxy (C 1 -C 4) alkoxy group, ŃO 2) phenyl radical or a 5- or eight-membered aromatic heterocyclic group in which 2 members are N, or one member is N and one member is O or S, or one member is N, S or O and the other members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indole, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl , morpholinyl; or c) an amino acid group of formula III -NH- / CH ₂ / _m -CH / R / -CO- / 111 / where m is an integer from 1 to 11 and R is ΝΗΧ, OX, SX, ΝΧΥ, -NH / H / -C / 0 / -CH? -X ', -N / H / -C / O / -CH ₂ -OX ¹ , -N / H / -C / O / -X ', -N / H / -C / O / -CH = CH-X * or -N / HAC / Cy-O-CIM ¹ , in which X represents a hydrogen atom, an unsubstituted or substituted benzoyl group, an unsubstituted or substituted cyclohexyloxycarbonyl group, an unsubstituted or substituted benzyloxycarbonyl group, a 2-, 3- or 4-pyridylmethyloxycarbonyl group, or a tosyl group, Y represents a C 1 to C 14 alkyl group or an aryl (C 1 to C 14 alkyl group) and X ¹ is (cc) phenyl, (β) with 1, 2 or 3 substituents / substituents: halogen, trifluoromethyl or nitro, substituted phenyl, (γ) naphthyl, (0) benzo [b] thienyl, (ε) pyridyl or (η) pyrazinyl. 8. The method according to p. The process of claim 7, wherein the amino acid AnBnOH is wherein An is a) a group - Ai - _A2 - A3 -, wherein Ai represents an α-amino acid / C₁-cesium-alkyl side chain; A ₂ is a ω-amino acid residue of formula II wherein n is an integer from 1 to 6; A3 is an α-amino acid residue with a side chain; or b) the group -A4 - A5 in which A4 is a ω-amino acid residue of formula II in which n is an integer from 1 to 6 A5 is a cc-amino acid residue with a side chain; or c) amino acid residue I of the formula / c ΠΙ, where m is 1,2,3 or 4, and R is -ΝΗΧ, ΝΧΥ, -nh / h / -c / o / -ch ₂ -x ', -n / h / -c / o / _{-ch 2} -ox *, -Ν / Η / -0 / 0 / -Χ ¹ , -N / H / -C / O / -CH = CH-X * or -n / h / -c / o / -o-ch ₂ -x * 9. The method according to p. 8. The process of claim 8, wherein the amino acid AnBnOH is wherein An is a) group - At - A ₂ - A3 - in which 168 456 Ai is Ala, Gly, Phe, Val, Ile, Leu or Nle, or their D-forms, preferably Gly, Ala or D-Ala; AND? represents a ω-amino acid residue of formula II. wherein n is 2, 3 or 5; a ~~ _____ t \ nt, "o atp tzu ~ r> / -ί, _λ τλ c ^ nu-i / τ ~> τ., .. Ph ezDa-pa mc, noik ^, 't-nAC-f nc, vua, wna, lzi / jlui /, je-oci / jj / a /, ly-D —tv ^ ł, Tyr (Bzl), D-Tyr (Bzl), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His or D-His, preferably phe, Tyr, Cha, Nal or (4-NO2) Phe; or b) the group -A4 - A5 - in which A4 is a ω-amino acid residue of formula II in which n is 2, 3 or 5; A5 means Phe, D-Phe, 4-NO ^ -Phe, Cha, D-Cha, Ser / Bzl /, D-Ser / Bzl /, Tyr, D-Tvr, Tyr / Bzl /, D-Tyr / Bzl, Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (Bzl), His, D-His, Glu (Bzl) or D-Glu (Bzl), preferably Phe, Tyr, Cha, Nal or / '4-NO2 /' - Phe; or c) an amino acid residue of formula III wherein m is 1, 2, 3 or 4 and R is as defined in claim 1; 8, with X being hydrogen, unsubstituted or substituted by chlorine, methoxy or a (C 1 to C 3) alkyl benzoyl, cyclohexyloxy or methyloxycarbonyl group, unsubstituted or substituted by methoxy, nitro, trifluoromethyl or cyano benzyloxycarbonyl group, preferably benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- or 4-trifluorometylobenzylokarbonylową albo4 nillsiaΞ / vs] C ΰOl'OaVScrryk) OLA ottUϊ5zezaLgkV lb ^ ^ ^ tyofcklvkαibonviswą4 itlobenzyloksykarbαnylową01bs2-head C-trifluorometylobenzyloksykarbonylową, Y represents a Ci to Ci4 alkyl or / Ci to Ci4-alkyl / phenyl, preferably benzyl or phenylethyl; and X ¹ is a phenyl group or a mono- or di-substituted phenyl group, 2-pyridyl group, 2-pyrazinyl, 3-benzo [b] thienyl, or 2-naphthyl. i0. The method according to p. A process as claimed in claim 1, characterized in that the amines and the acid AnB nOH are used, in which: An is the group - Ai - A2 - A3 - where Ai is Gly, A2 is Aca, pAla, Apen, Abut, Gly or a covalent bond, and A3 is Phe, Phe (4-NO '), Tyr or Tyr (Bzl); or An denotes the group - A4 - A5 - in which A4 stands for pAla, Aca, The, Aund, Btu or D-Btu, a A5 is a covalent bond, Phe, D-Phe, Phe (4-NO2), Tyr, Tyr (Bzl) or Cha; or An is an amino acid residue of formula III -NH- / CH2 / mCH / R / -C0- where m is i or 4 and R is the group -NHX where X is H, Z, Bz, Menoc, / 4-NO2 / Z or Tos or An is X2-Lys-, where χ2 is one of the following groups ABOUT O '^ \ y li 168 456 Bn is Arg, D-Arg, Lys, Orn, or Ctr; and the CnOH is Cha, Phe, Ser (Bzl), Tyr, Tyr (Bzl), or Tyr (Me); D-Ala, Pro or D-Pro is used as DnOH; Gly is used as EnOH; or Dn and En together are L-Clg, D-Clg or D-Btu; Arg or Lys are used as FnOH; as GnOH, Ile, D-Ile, Nle or Met is used; Asp, D-Asp or Gly is used as HnOH; Arg or D-Arg is used as InOH; and as KnOH, Ile is used. 11. The method according to p. The process of claim 10 for the preparation of the compound of formula 1 in which An is -Gly-pAla-Phe-, -Gly-eAla-Tyr / Bzl / -, - β-Ala-Phe, - β Ala-Phe / 4-N O2 / -Ly s -, - / 4-NO2 / Z-Lys-, ABOUT Bn is Arg, Lys, Ctr or Orn; Cha or Phe is used as CnOH; as DnOH is used for D-Ala; Gly is used as EnOH; Arg is used as FnOH; Ile or Met is used as GnOH; Asp is used as HnOH; Arg is used as InOH; and as KnOH, Ile is used 168,456 by coupling successive sequences. 12. The method according to p. The process of claim 1, wherein to produce the cyclopeptide of the formula below -pAla-Phe-Arg-Phe-B-Ala-Gly-Arg-Iie-Asp-Arg-Ile-Gl The following amino acid derivatives are used Fmoc-Ile-OH, Fmoc-Arg / Mtr / -OH /, Fmoc-Asp / tBu / OH, Fmoc-Gly-OH, Fmoc-D-AlaOH, Fmoc-Phe-OH and Fmoc-pAla-OH. 13. The method according to p. The process of claim 1, wherein to produce the cyclopeptide of the formula below - ^) Ala-Tyr / Bzl / -Arg-Cha-D-Ala-gly-Arg-ile-Asp-Arg-Ile-Gl. Fmoc-Tyr / Bzl / -OH and Fmoc-Cha-OH are used. 14. The method according to p. and wherein to prepare the cyclopeptide of the formula below - [iAla-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Il Fmoc-Ile-OH is used instead of Fmoc-Met-OH. 15. The method according to p. The method of claim 1, wherein Fmoc-Lys / BOC / -OH and Fmoc are additionally used to produce the cyclopeptide of the following formula a-Phe-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- -Ile-OH instead of Fmoc-Met-OH. 16. The method according to p. The process of claim 1, wherein to produce the cyclopeptide of the formula below - ^ Ala-Phe / Ą-NO ^ / - Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Il Fmoc-Cha-OH and Fmoc-Phe / 4NO2-OH are used instead of Fmoc-Phe- OH. 17. The method according to p. The method of claim 1, wherein Fmoc-Ctr-OH and Fmoc Ile-OH are additionally used to prepare the cyclopeptide of the following formula la-Phe-Ctr-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- instead of Fmoc-Met-OH 18. The method according to p. A process as claimed in claim 1, characterized in that in order to prepare the cyclopeptide of the following formula (4-NO ₂ ), Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Il is used (4NO2 / Z-Lys) Fmoc / OH instead of BOC-Lys / Fmoc / OH; Fmoc-Ile-OH for Fmoc-Ile-OH and Fmoc-Cha-OH for Fmoc-Phe-OH. 19. A method according to claim 1, characterized in that to produce the cyclopeptide of the formula below X ² -Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile168456 where X ² is t- r use X-Lys-Fmoc-OH instead of-2-pyridylacetyl Lys / Fmoc / OH . 20. The method according to p. The process of claim 1, wherein Z-Dep (Fmoc) is used to prepare the compound of the following formula (4-NO ₂ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Il. OH instead of BOG-Lys / Fmoc / '-OH. 21. The method according to p. A process as claimed in claim 1, characterized in that in order to prepare the cyclopeptide of the following formula (4-NO ₂ ) Z-Lys-Orn-Cha-D-Ala-Arg-Ile-Asp-Arg-Il, Z-Dep / Fmoc / -OH is used instead of BOC-Lys / Fmoc-OH.