CZ61893A3 - Cyclopeptides, process of their preparation and their use as medicaments - Google Patents

Abstract

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

Description

Technical field

I * ¹

AND;

The invention relates to novel cyclopeptides which are built up of natural and unnatural amino acid residues. their manufacture and their use as pharmaceuticals. The peptides are ANP-agonists.

The novel cyclopeptides represent partial sequences, partial sequences discontinuously linked to each other, modified partial sequences and analogues of so-called atrial natriuretic factors, ANPs, or atrial natriuretic pentides.

BACKGROUND OF THE INVENTION

ANP is mainly synthesized in cardiac atrial muscle cells. there it is also deposited as prohormone and released by mechanical irritation due to increased wall tension. It acts as a vascular relaxant, lowers blood pressure, has diuretic and saluteric effects, increases glomerular filtration, reduces plasma volume and increases hematocrit, decreases plasma renin activity and plasma aldosterone levels, acts smasmolytically on intestinal smooth muscle and broncholytically. The action is mediated by specific receptors.

In this specification and claims, abbreviations have been used according to the recommendations of the IUFAC-IUB Joint Commission of the Biochenical Nomenclature (Sur. J. Biochem. 138, 9-37 (1984)). ^r sing were other abbreviations are explained below.

Aund ω-aminoundecanoic acid Abut .alpha.-aminobutyric acid Aoc O-Aminooctanoic acid Apen b -ammopentanoic acid Aca .Beta.-aminocaproic acid Aib ¢ -Amino-butyric acid Ala alanine Ala -alanine Arg arginine Asp aspartic acid Azt 0 It

Boom tert -butyloxylmethyl BOC tert-butyloxycarbonyl Btu 3-Amino-1-carboxymethyl-pyrrolidin-2-one Bzl benzyl Bz benzoyl Cha CyclohexylBlanin Cle cycloleucine Clg 3-amino-1-carboxetyl 1-hexahydroazepine- ______ 2-q.n '' .......- --.....- - --- - -.....- - ' Ctr F,' citrulline Dap 2,3-L-diaminopropionic acid DMF ' N, N-dimethylformamide DPPA diphenylphosphoryl azide DCC dicyclohexylcarbodiimide DIC diisoprop.ylcarbodiimide piy ...... ..... glycine <- ......... His histidine HOBt 1 -h.ydroxybenzotriazole Ile isoleucine Leu leucine Lys lysine

-3ftť ί ·>

2Menoc menthyloxycarbonyl

Me methyl,

Met methionine

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

Na 1 -naphthylalanine

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

Orn ornithine

Phe phenylalanine

Pmc pentamethylchromansulfonyl

Ser serin

The ε-amino-N-carboxy-tetrahydroisoquinolin-1-one

Thi

ch ₂ -gh (nh ₂ ) -cooh

It with

Trc

Trt trityl Tyr tyr osin Wall valine OF benzyloxycarbones1

The term amino acid includes, unless the context clearly indicates otherwise, natural and unnatural amino acids, as well as their D- and L-forms. The term -amino acid also includes -d and substituted amino acids.

and

If the amino acid is given without a prefix (e.g. Drn), it represents the L-form of the amino acid. D-Eorms' is clearly labeled (eg, D-Grn).

SUMMARY OF THE INVENTION

The invention relates to cyclopeptides of the formula I with aN? agonist activity

- Ai-Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn-j · (I)

Wherein the sequence of members 3n to Kn is the sequence of amino acid residues of hNP

- (g) (27) -Phe (S) -Gly (5) -Gly (10) -Arg (11) - (1 2) -j ^ sp (13) - Arg (14) -Ile (1 5) ) - or its spatially structural and functional equivalents ε Ai represents a spacer group which connects 3n with Kn and thus affects the spatial structure of these molecules so that the cycles of the cycles to 5u n? the recipe for rye, and their pharmaceutically acceptable salts.

Preference is given to cyclopeptides in which the spacer group A 1 in the portion downstream of the member 3n contains an aromatic or cycloaliphatic residue.

Most amino acid residues may be in the form

D- or L. Preferred are eccleptides in which the members or most of the members are 5n, Cn, En, En, Gti, Hn, in and Kn in the L-form.

The er-C-atoms of the An and Kn at a distance of 5 to 15 maintain Λ-C-atoms of 3% gstroms. (Conformation from 2D-NVR measurement in aqueous solution, results as boundary conditions for simulation of molecular dynamics).

It does not bind to AJP receptors but affects the ability to bind to receptors and hence the pharmacological activity of the cyclopeptide of formula (I).

irí,

The spatially structural and functional equivalents of the amino acid residues of AIP include amino acid residues or peptide templates (as well as L-forms as well as D-forms), which cause the cyclopeptides of formula 1 to bind to α-receptors. Investigations carried out so far have shown that, for example, the sequence (3n-Kn) -g-Ohs-D-AlaOly-Acg-ile-Asp-Arr-He- shows very good receptor binding and pharmacological activity values. Individual members of the sequence are replaceable residues of similar spatial structure and / or function, whereby the ability to bind to receptors is more or less influenced and the degree and, in many cases, pharmacological activity varies within the known AJP-agonist activity. Variations in the Members are the type, size and duration of pharmacological activity that can be influenced. If more than one of the members 3n to Kn changes, then, to the knowledge of the art, the change in pharmacological activity consists of changes corresponding to the individual variations. The following list presents a structurally similar example. d, y the relationship between the non-receptor binding ability and the sequence of members of the cyclopeptide of general formula I. (Test description is given below under the title AJP-receptor binding).

Compounds labeled ^{M 1} have an IC 2 -value of less than 5.10 mol in the above-mentioned N 2 -receptor binding assay, the pure compounds having less affinity.

t

-6]

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

B *).-EAla-Phe-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile

BAla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile- »h- *

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

E-Hap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

G*)

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

H *)

-BAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile-Phe _r Ala-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D -Arg-Ile-i

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

L-Ba-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-i

As already mentioned, the amino acid cutout includes natural and non-natural amino acids. Preferably, unnatural amino acids, unless explicitly stated narrower, are based on their molecular weight and / or molecular weight. side chain length, such that they correspond to the size of the natural amino acids.

ⁱⁿ such salts are salts with physiologically acceptable inorganic or organic acids such as e.g. HC1 H3R ^{H 2-C} 4 '^ 3 ^ 4' ^ ^y if ^on maleic acid, fumaric acid, citric acid, tartaric acid acetic.

Chirality centers in new peptides may have kon-γ figuration. fi, 3, or R, S.

The terms t, * ´ n and in correspond to øg (27), -Arg (ll) or §? § (14) or their spatial structure. and functional equivalents. Βη, Κη and ln can independently be% amino acid residues with two basic side chains or preferably one basic side chain. A basic side chain is preferably an alkyl or cycloalkyl side chain containing from 1 to 4 (preferably 1 or 2) basic groups. Suitable basic groups are, for example, -NH-, = NH, -NHg,

-HN-G (NH) -WH ₂ , -C (NH) -NH ₂ . Preferably, at least one of the basic side chain groups is divalent. Further preferred are side chains whose first basic group is linked to a -carbon atom, a -amino acid, or a carbon atom which is further away in the peptide chain. Preferred alkyl side chains of 1 to 6, especially 3 or 4 carbon atoms with side chains cykloalkvicvé -) - ((TA) - (CH ₀₎ -, wherein xavx ys. <Y are each independently 0,1 or 2, and (CA) is C 5 -C 6 cyclo-8alkyl, with basic groups at the end of the side chain being preferred.

The Gn member corresponds, as already mentioned, to Phe ¢ 8) ANP or its structural and functional equivalents. Gn can be a α-amino acid residue with two lipophilic side chains or preferably one lipophilic side chain. 2a, a lipophilic side chain at this position is considered to be an alkyl side chain of 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, especially 1 carbon atom). These alkyl side chains may contain one or two oxy (-O-), thio (-S-) -O (O) O- groups. These alkyl side chains carry one or two radicals. These radicals are independently cycloaliphatic (preferably cycloalkyl) radicals containing 3 to 10, preferably 4 to 7, carbon atoms. The aromatic moiety is preferably phenyl, naphthyl, substituted (e.g. NOx, hydroxy, phenyl (C ^^) alkyloxy or _t C 4 alkoxy) phenyl or 5- or 6-membered aromatic or benzofused heterocycles also comprising. 2 N atoms or as one member. h ε one ring member O or S, or as ring member containing N, S or O and the other ring members are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, p.yridazin.yl , indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl.

Bn ε En corresponds to Gly (9) or Gly (10) of VNP or its spatially structural and functional equivalents.

Bn a En can independently be ns yourself meaning Gly or rest c \ - . o η? ** ** / 3 p? lj * t ¹ 2 2 * n ap od obuje prostorovou structure native amino acids (Glv) , or Bn and En may

O.

from the n-position means (O-amino acid residue or peptide template

Jn and En are preferably suitable amino acid residues which, according to statistical analysis of Chou-a asman (3iophysical Journal, Vol. 26, 1979, 367-3-4), are often found in the conformation. Preference is given, for example, to amino acids which occur with an increased frequency at the positions i + 1 and i + 2, in particular those with frequencies Ο, ύό (Table 1 of said publication).

Sweating with suitable peptide temples is understood to be those having co-conformation of β-treatment.

The members Gn and Kn correspond, as already mentioned, ,, u * 4et (12) or Ue (15) AN? or spatially thereof ^; structural and functional equivalents. Gn and Kn can each independently be o (-amino acid residue with always two lipophilic side chains or preferably one lipophilic side chain. Lipophilic side chain at these positions means alkyl.

a side chain having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, in particular a chain having at least 3 carbon atoms.

These alkyl side chains may additionally contain 1 or 2 oxy (-O-) or thio (-3-) groups (such as in methionine). These side chains may also contain 1 to 2 alkyl radicals.

member hn corresponds as already mentioned Asp ί 1 3) AN? because of its spatially structural and functional equivalents. Jlen acts as a spacebar. Hn can be a κ-amino acid residue, namely a Gly or a residue that bears no functional group in the side chain, or -COOH ε / or • i / suitably the alkyl side chain is a chain of 1 to 6 (preferably 1-3) atoms carbon which may carry the phenvic group e / ns. CGC '*** 2 1 -4 ^not ' °° 'fy!

\ ¹ JII

- + v

-10Λι means, as already mentioned, the gut group. This group may be

(a) the group - A - A - Ay

b) the group -A 1 -A 1; c) the amino acid residue of formula III

-NH- (CH 2) -CH (p) -CO 2 m (III)

A 1 can be Gly or an amino acid residue with two side chains, or preferably one side chain. These side chains are not desirable. functional groups. Preferably, such a side chain is a branched or unbranched alkyl side chain of 1 to 6 carbon atoms.

A 3θ covalent bond or a 6J-amino acid residue of formula II

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

A 1 can be a Λ-amino acid residue with two lipophilic side chains or preferably one lipophilic side chain. A lipophilic side chain at this position is to be understood as meaning an alkyl side chain with carbon atoms (preferably carbon atoms of 4 to 4 carbon atoms, in particular 1 carbon atom). These alkyl side chains may contain one or two px (-O-), thio (-3-) or -C (O) O-groups. These alkyl side chains carry one or two residues. These radicals are independently cycloaliphatic or aromatic radicals. The cycloaliphatic residue (preferably a cycloalkyl residue) contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic residue is preferably phenyl, naphthyl,

-1 1-substituted (e.g., hydroxy, phenyl (C?) - alkoxy, or _C1 ^ alkoxy} phenyl or 5- or 6-membered optionally also benzofused aromatic heterocycle in which two members of the ring are N or one component is N and one O or S, or one member is N, S or O and the others are C, preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, rnorf olin.yl.

A may be a pentide compound or an amino acid residue of formula II

-NH- (CH ₀₎ n -C02 (TI) wherein n is an integer of 1 to 11 (preferably 1-6); peptide templates include groups such as C1g, 3tu, The and Tre.

it may be a covalent bond or an amino acid moiety with two lipophilic side chains or preferably one lipophilic side chain. A lipophilic side chain at this position means an alkyl side chain of 1 to 7 carbon atoms (preferably 1 to 4 carbon atoms, especially 1 carbon atom). The alkyl side chain may contain one or two oxy (-O-), thio (-S) or -C (O) O-groups. This alkyl side chain carries one or two radicals. These radicals are independently cycloaliphatic or aromatic radicals. The cycloaliphatic (preferably cycloalkyl) radical contains 3 to 10, preferably 4 to 7, carbon atoms. The aromatic residue is preferably phenyl, naphthyl, substituted (e.g., NCL, hydroxy, phenyl (C1-alkoxy or alkoxy) phenyl) or a 5- or 6-membered optionally benzocondensed aromatic heterocycle,

Wherein two ring members are N or one N and one O or S, or one member is N, 3 or O and the other are C, preferably thienyl, furyl, p-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxezolyl, morpholinyl.

Λι can also be an amino acid residue of the formula III -NH- (O '- (CH 2) - CG- (III) where a is an integer from 1 to 11 and R is NHX, ΟΧ, SX, ΝΧΪ, -NH (H) -G ( 0) -GH ₂ -X ¹

-N (H) -C (O) -CH ₂ -O-X ', -N (H) -C (Ο) -Χ',

-N (H) -C (O) -CH = CH-X 2 or -NCHO-CH 2 -O-CH 2 -X ¹ , wherein

X is hydrogen, unsubstituted or substituted benzoyl, unsubstituted or substituted cyclohexylcarbonyl, unsubstituted or substituted benzyloxy. bonyl radical, 2-, 3- or 4-pyridylethyloxycarbonyl radical or tosyl radical,

Y is a C1-C14-alkyl radical or an aryl-C1-C14-alkyl radical;

X 4 is (4 ') phenyl, (fy) 1, 2, or 3 substituents (substituents: halogen, trifluoromethyl or nitro) substituted phenyl, (n-J, phenyl, í)) benzo (b). ... thienyl ,. ( ^e ) pyridyl or pyrazinyl.

Preferred is an amino acid residue of formula III, wherein m is 1,2,3 or 4 and R is -NHX, -ΝΧΎ,

-NH (H) -C (0) -CH _about -X ^1,

-N (H) -C (O) -CH ₂ -OX ¹ ,

-N (K) -C (Ο) -Χ ',

-N (H) -C (O) -CH = GH-X ¹ or

-NdO-ClO-O-CHg-X ¹ .

Preferred are those cyclopeptides of the above formula wherein

3n, Fn and In independently of each other are Arg, D-Arg, Lys, D-Lys, Ora, D-Orn, homo-Ag, D-NH-Arg, Dep, D-Dap or 4-amino preferably Arg, D-Arg, Lys, D-Lys or Drn,, (Z

He. It is Phe, DP-E, 4-NO ₂ -Fhe, the GHA, D-Ser (3zl), Tyr, D-Tyr, TyrÍBzl) * hi, D-Thi, Asp (3zi), D-.asp (3zl ), or D-Glu (3zl), preferably Fhe, Gha or U-NOgJ-Phe,

D-Chs, SsrOzl)

D-Tyr (3zl), Nel, D-Nal, his, D-His, Glu (3zl) ,. Tyr, Nel, T.yrOzl)

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

En is Gly, Asp or · Α, η, or

Dn and Ennole denote a CG amino acid residue of the formula -NH- (CH-) ₂ 5 -GO- or a peptide template, preferably 3tu, Clg, The or Tre or their D-forms, especially D-3tu,

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

Kn is HOOC-CH3. The? -GHIN-1-CO-, D-forms of this residue, Gly, Ala, D-Ala, Asn, D-Asn, Fhe or D-5, preferably Asp,? Glu or Gly,

Aq means

s) group - A. - Au, ·

And he's A, Gly his D-form

A ^ -j where

Fhe, Vel, preferably

Ile ^- , Leu or ^ le or Hv, Ala or D-Ala,

-14 is an amino acid residue of formula II wherein n is 2, 3 or 5, is Phe, D-Phe, 4-NC2-Phe, Cha, D-Cha, 3er (3z), D-Ser (3z), Tyr, D-Tyr (3zl), Tyr (Bzl),

Nal, D-Nel, Thi, D-Thi, WSzl), D-Asp (3zl),

His or L-Kis, preferably Phe, Tyr, Cha, Hal or (4-NO2) Phe, or

b) a -A 4 -A 5 - group, wherein the ch-amino acid residue of formula II, wherein n is 2,3 or 5, is Phe, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha, Ser ( Szl), D-3er (3z), Tyr, D-Tyr, Tyr (Szz), D-Tyr (3z), Nal, D-Nal, Thi, D-Thi, Asp (3z), D-Asp (3z) , His, D-Hia, Glu (3zl) or D-Glu (3zl), preferably Phe, Tyr, Cha, Nal or U-NC-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 S wherein X is hydrogen, unsubstituted or chloro, methoxy or (C1 to C3) alkyl-substituted benzyl, c-cyclohexyloxy -. or a menthyloxycarbonyl radical, unsubstituted or methoxy, nitro, trifluoromethyl or acid-substituted benzyloxycarbonyl radical, preferably benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- or 4-trifluoromethylbenzylcarbonyl or 4-nitrobenzyloxycarbonyl

-15-benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or

2- or 4-trifluoromethylbenzylox, ycarbonyl,

Y represents a C 1 -C 01 -alkyl radical or a (C 1 -C 01 -alkyl) phenyl radical, preferably benzyl or phenylethyl;

X represents phenyl or mono- or di-substituted phenyl, 2-pyridyl, 2-pyrazinyl, 3-benzo [b] thienyl or 2-naphthyl, especially those where:

Znamenáι denotes the group where

And, is Gly,

A 1 is Aca, R 1, Ala, Apen, Abut, Gly, or is co-. valentine binding and

Behold, he, Phe (4-NC ₉ ), Tyr or Tyr (3zl), or

An represents a group -A 1 -A 1 -, wherein

A4 is (Ala, Ac-a, The, Aund, 3tu or D-3tu, and A 1 is a covalent bond, α, D-Phe, PheU-NC 4),

Tyr, Tyr (3zl), or Cha, or

An is an amino acid residue of formula TTx

-NH- (CH ₉ ) -CH (R) -OC-, wherein m is 1 or 4 and R is a group

-NHX, where H is H, 2, 3z, 4-eno, (4-NO 2) Z, Tos, is £ or An is X -Lys-, wherein ¹

X is one of the following groups

-1 6-

Preferably, the peptides of formula (Ia) are

and salts thereof, wherein * 2 is Aund,

Apen,

Abut or

Gly or covalent bond is Phe,

Phe (4-NO _c )

Gha,

Tyr or T.yr (3zl),

3n is A _r g, ^x yr or Tyr (3zl ·),

Dn is D-Ala,

For or

-v -n

J-rro »

2n is Gly, or

Gn. and Gn from below form

D-3tu,

Pn is Arg or Lys,

Gn is Tle Met

Hrr is Agp or

Alb,

In is Arg,

Kn is Ile and

And, it's Gly.

Particularly preferred are cyclopeptides and optionally salts thereof, wherein

A, is a α-amino-alkanoic acid residue of the formula

-nk- (ch ₂ ) ₂ _ ₄ -co-,

Aj is Phe, Tyr, Cha, Nal or 4-NO ₂ -?

3n, Pn and In independently of each other are Arg, D-Apg, Lys,

D-Lys, Orn, or Ctr,

(Phe, Cha, Tyr, Nal or TyrSzl),

Dn is D-ALa, Gly, Phe or D-Phe, ..........

... rfi ll ..... i * '

2n is Gly or ALa, or

Dn and Pn together form D-3tu,

Gn and Kn are independently Ile, N-et, Nle or Leu, Hn is Asp, Glu or Gly with Aj is Gly, Ais or D-Ala, especially those where

-19 is β-Ala,

Apen or Abut,

A * is Phe,

Phe (4-NO ₂ ), Cha or Tyr,

3 _n is Arg,

Cn is Phe,

Cha,

Ty _r n _e bo £ yr (3zl),

Pn is D-Ala ,,

Pn is Gly or Pn e i In total D-3tu, Pn Yippee Arg or ^L .ys, θη Yippee Ile, Jet or Nle, hn Yippee As o, ± n Yippee Ar- ;, Λ · η 4 a at Ile a 1 of* "

AND

Particularly preferred compounds of the invention are:

1.

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

2.-Ac-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile->

3. r-Bala-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

_R 4th Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Il ^

-215. pBAla - Phe - Arg - Phe - D - Ala - Gly - Arg - Ile - Asp - Arg - Ile - Gly - i

6. <-Phe (4-NO2) -Arg-Phe-D-Al and -Gly-Arg-11 le-Asp-Arg-11 le-Gly-,

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

8. j-Bala-Cha-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-j, -Bala-Phe (4-NO2) -Arg-Phe-D -Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

10.

j-BAl and -Phe (4-NO 2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-j (-BAla-Tyr-Arg-Cha-D-Ala-Gly -Arg-Ile-Asp-Arg-Ile-Gly

12.

-BA1a-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ac-Phe-Arg-Phe-BAla-Arg-Ile-Asp-Arg-1 le-Gly

-2214. -Aca-Phe-Arg-Phe-Abut-Arg-Ile-Asp-Arg-1le-Gly-

Ί

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

16., -Abut-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Gel-Gly-, 4. pGly-Phe-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-,

18. j-Bαla-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly 19. pAca-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-1le-Gly

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

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

22.-aa-Phe-Arg-Phe-D-Ala-Gly-Arg-Aib-Asp-Arg-Ile-Gly-j

23. -flAla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Aib-Arg-Ile-Gly ^. r-Bala-Phe-Arg-Phe-L-Btu-Arg-Ile-Asp-Arg-Ile-Gly-

25. Alpha-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-Ile-Gly-2 3-

26. j-Bala-Phe-Arg-Phe-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly- 27 Mar: -phaAla-Phe-Arg-Phe-D-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly- 28. f-Tyr-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly- 29. -Tyr (Bz 1) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-j 30. * 'i' -Phe-Arg-Tyr-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-. ......... 1 * ³ Ί -Phe-Arg-Tyr (Bzl) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-j 32. -Bala-Phe-Arg-Phe-L-Clg-Arg-Ile-Asp-Arg-Ile-Gly- 33. -Bala-Phe-Arg-Phe-D-Ala-Gly-Arg-Nle-Asp-A.rg-Ile-Gly- |

and salts thereof

-24Cyclopeptides of formula (1b) are preferred.

- N 2 - N 2 -Sn-Cn-Dn-En-Pn-Gn-Hn-In-Kn salts thereof where t

And, is Aund,

Acs,, - Al and,

Gig, The, 3tu or D-3tU ',

A ^ is Bhe, D-Phe,

Phe (4-NO ₂ )

Cha,

Tyr,

Tyr (Bzl) or covalent bond,

3n is Arg, _______ ..........................—- Ctr,

Lys or covalent bond,

Cn. is Phe,

Cha,

Ser (3zl) or

Tyr Oďe), -

Dn is D-Ala,

Gly or

Az t, ..... ...

'? Γ * n wly _f

Pr * is Arg or ' ^£ ys, -25Gn is He, G-Ile,

Met or Nle,

Nn is Asm, D-Asp,

Gly or covalent bond, ² η is Arg or L-Arg and

Kn is Ile.

Particularly preferred are cyclopeptides, or salts thereof, wherein

Also. CG - aminoalkanoic acid residue of the formula

-NH- or when A 1 represents a covalent bond,

Gig, The, 3+ or G-3TU,

A ^ is £ he, Tvr, Cha, Nal or 4-NCh-Fhe,

Bn, Fn and in are independently Arg, 2-Arg, lys, D-Lys, Orn, or Gtr,

Cn is Fhe, Cha, Tyr, N.al or Tyr (3zl),

Gn is G-Ala, Gly, Fhe or G-Phe,

Fn is Gly or Ala or

Gn and En are together, -i; ·? or i-eu 2

ΟΟτΟΟ ^J iVj

-26A is β-Ala,

Anen nebo

Aout, or if it is a covalent bond, means Olg, The, 3tu or 3-3tu, * ^{9 Phe} »4

- ^p h (4-hOJ, *

Chs or Tyr or

3n is A-g,

He's Phe,

Cha,

Tyr or Tyr (3zl),

Dn is D-ALa,

En is Gly or

Dn and En mean sool

D-3tu,

Fn is -Arg or Tys,

Gn is Tle, aiet or Nle

En is 4p, ^χ η is a

Preferred compounds of the invention are:

t

I ϊ

-Aund-Phe-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg- I le-Gly3. _1- Ac-Phe-Arg-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-IIe-Gly- ₁ . _r Ala-Phe-Arg-Phe-D-Bfcu-Arg-Ile-Asp-Arg-Ile-Gly-285th j-Bala-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-IIe

6. -Bala-Phe-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile- 7. r-Aca-Phe-Lys-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-η 1 1 8, [-Aca-Phe-Lys-Phe-D-Ala-Gly-Lys-lle-Asp-Arg-lle- O '1 Aca-Phe-Arg-Cha-D-Ala-Gly-Arg-Xle-Asp-Arg-X le- *

10. Ac-D-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile 1 11. Aca-Cha-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ilej 12. | -Bla-Phe-Arg-Cha-D-Ala-Gly-Arg-River-Asp-Arg-Ile- - 13 . -Bala-Phe-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile- 14. -Bala-Phe (4-NO2) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Iie ]. 15 Dec -Bala-Phe-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-

-2916. i-Clg-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

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

18. <-FaAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-i

19. f-Bala-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-i

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

I-BAla-Phe-Ctr-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

22. pThc-Phe-Arg-Cha-D-Ala-Gly-Arg-Arg-Ile-Asp-Arg-Ile pClg-Arg-Cha-D-Ala-Gly-Arg-Arg-Ile-Asp-Arg-Ile

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

25. pAund-Phe-Arg-Phe-D-Ala-Gly-Arg-Arg-Ile-Asp-Arg-Ile-i

26. r-Ac-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile-1

-3027. t-Aca-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-I; | -Aca-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-11e- |

29. i-Bala-Phe-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile 30.

31.

[-Aca-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile-B] -Ala-Arg-Phe-D-Ala-Gly-Lys-Nle-Arg-Ile-i

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

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

3-4 ™> BATa-Gly-Ser (Bzl-D-Ala-Gly-Lys-Nle-Asp-Arg-Arg-i-Aca-Gly-Ser (Bzl) -D-Ala-Gly-Lys- Nle-Asp-Arg-Ile36 (-Baa-SerCis) -I-Aia-Giy-Lys-Nle-Asp-Arg-Ile-Aca-Ser (Bzl) -D-Ala-Gly-Lys-Nle -Asp-Arg-Ile-j

43. t-Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Gly-Arg-Ile-. · '·. j-Aca-Phe-Arg-Tyr (Me) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

45. -Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile- • 46. Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-D-Asp-Arg-Ile- $ Ac-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-j 48. -Aca-D-Ph-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-

-3249.

50.

51,

52.

53.

54.

'55.

-5-6-. 57.

p-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Bla-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile- | | -Bala-Phe-D-ArgrPhe-D-Ala-Gly-Arg-Ile-Asp-D-Arg-Ile-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile _r BAla- Phe-D-Arg-Ph-D-Ala-Gly-Arq-Ile-Asp-Arg-Ile-i

Bala-Phe-Arg-Cha-Azt-Gly-Arg-Ile-Asp-Arg-Ile

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

Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Asp-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile and salts thereof.

The cyclopeptides of the formula ## STR3 ## are the salts thereof, wherein

Ai is H-Lys,

Z-Lys 3z-Lys Menoc-Lys (4-1 ^) Z-Lys 3z-D-Lys Tos-Lys H-Dap or Z-Dap,

3n is A? G _r ^l y>

Fhe or Grn,

Gn is Fhe ·,

Chs or 3er (3zl),

Dn is D-Ala, ^{Λ η} is Gly, or

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

Fn is Arg or lys,

Gn is Ile neoo iAe,

-34Hn is Asp,

In is Arg and

Kn is Ile.

Particularly preferred are the cyclopeptides or salts thereof, wherein

An aminoalkalkyselinový is a radical of formula -NH- (CH _{2) n.-CH} (R) -CO-, wherein n is 1 or 4, R is NHx or -NXY

X is benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2- or 4-trifluoromethylbenzyloxycarbonyl, cyclohexyloxycarbonyl or menthyloxycarbonyl and Y is benzyl or phenylethyl,

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

He is Fhe, Oha, Lyr, Nal, TyríSzl) or 4-NG -> - he,

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

En is Gly, Ais or Phe, or

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

Gn and Kn are independently Ile, et, Nle or

Leu a

Kn's Asp, Glujiebo Gly, ....... ......, ........

especially those where

Ao j e H — Ly s ....... ..... .....

Z-Lys 3z-Lysphenoc-Lys, (4-NO ₂ ) Z-Lys

3-L-Lys Tos-Lys

-35H-Dap or Z-Dap,

3n is Arg, Kys, Orn, or Phe

Cn is Phe,

Cha or Ser (3zl),

Dn j e D- Al a,

En is Gly or

Dn and En form together

L-Clg or D-Clg,

En is Arg or ^L ys,

Gn is Ile or

Behold,

Hn is Asp,

In is Apg and

Kn is He.

The preferred compounds of the invention are:

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

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

3. Z-Lys-Arg-Ser (B21) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile4. Bz - Lys - Arg - Phe - D - Ala - Gly - Lys - Nle - Asp - Arg - Ile

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

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

-377.

8.

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

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

-i, 9 ·

10.

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

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

11.

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

12.

(4-NO ₂₎

13.

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

H-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle-Asp-Arg-Ile-15.

with

16.

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

17.

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

-3818. Bz-D-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile. Tos-Lys-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile

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

21, Z-Lys-Arg-Phe-L-Cl-Arg-Ile-Asp-Arg-Ile-i

22, Z-Lys-Arg-Cha-L-Cl-Arg-Ile-Asp-Arg-Ile-i

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

24. H-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ill-i. Z-Dap-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile and its salts,

Preferred are the cyclopeptides of formula I and salts thereof, wherein

Ai is as defined above,

3n is Arg, ^L .ys,

Phe or Orn,

Cn is Phe,

Cha or

Ser (Bzl)

Dn is D-Ala,

En is Gly, or

J, *

Dn and En are together as well

L-Clg or D-Clg,

En is Arg or Lys,

Gn is Ile or Nle,

Hn is Agp,

In is Arg and

Particularly preferred are cyclopeptides, or salts thereof, wherein

A 1 is an aminoalkanoic acid residue of the formula

-NH- (CH ₂ ) _n -CH (R) -CO-, wherein n is 1 or 4,

R is -NHiKi-C 6 J-CH 2 X ¹

-NKJ-C ¹ -C ¹ -OX ¹ -N (E) -C (O) -X ¹ -N (H) -C (O) -CH = CH-X ¹ or -NH 3 -C 6 O-OC 1 -X ¹ , wherein χ 1 is (a) phenyl, (b) i or 2 substituted phenyl, (o) 1- or 2-naphthyl, (d) 3-benzo / b / thienyl, (e) 2-pyridyl or (f) ) 2-pyrazinyl,

3n, Pn and In independently of one another are Ag, D-Arg. Lys, L-Lys, Orn, or Gtr,

Cn is Phe, Cha, Tyr, Ngi, Tyr (3zl) or 4-NO ₂ -Phe.,

Dn is D-ALa, Gly, Phe, or D-Phe,

Pn is Gly, Ais or Phe, or .Dn and Pn together are D-3tu, L-Clg, or D-Clg,

Gn and Kn independently of one another are Ile, ni, Nle or Leu and

H n is sp, Glu or Gly, especially those where

A 1 is -NH- (CH ₂ ) 4 -CH (R) -CO-, wherein R is as defined above and

..... -Pn-Cn-Dn-Pn ^ Fn-Gn-Hn-In-Kn- · means a string

Arg-Cha-D-Ala-Gly-Arm-Ile-Asp-Arg-Ile as supported by the examples.

The compounds of the invention are ANP-sgonist. ^d as a natural 4NP show

- specific and affinity binding to ANP receptors

- diuretic and saluretic properties

- blood pressure lowering effectiveness

- increase in hematocrit

- increase in cyclic GIŠP (G.WP: probable intracellular mediator (second messen. ger * '), which can be detected in plasma after increased ANP)

- increased glomerular filtration

- vascular relaxation efficacy

- broncholytic activity

- spasmolytic activity on smooth muscles, especially the intestines.

These properties of the compounds of the invention were individually tested as follows:

- 7 binding n with ANP-receptors

Binding to ANP receptors from ona-glomerulosis of bovine adrenal gland cells was determined by the method of Bilrgisser et al. (3iochem.3iophys.Hes.Commun.133, 1201 (1985)), modified according to Sttrgisser (2nd World Congress on 3iologicall Active Atrial Peptides, May 16-21, New York Am.Soc.Hypertens., Sbstr.3181, p. 209 (1987) with a commercially available kit from ANAWA, Wangen, Switzerland.

- Blood pressure lowering, diuretic / saluretic efficacy, increase in hematocrit, increase in cyclo_GMP

Focuses are performed on narcotized (Membutslemb) spontaneously hypertensive rats (Ivsnovss). Tracea cannula. Blood pressure is registered from A. crotrotis. via a pressure transducer (Ststhsm) n with a recorder (Wrtanabe ^ ulticcrder). Heart rate is pulled from the puizu grid

OU

.. 3.-4.-Ciiseca suostsn orovi or xenyio-42V.jugularis. The bladder is cannulated and urine is collected by another abdominal incision. The urine volume is determined gravimetrically. Sodium and potassium are measured photometrically, chlorine is determined by electrofiltration. Hematocrit is measured from erterial blood. Cyclic GL1P is determined from arterial blood by a commercially available reductive assay (I3L, Hamburg).

- Effect on glomerular filtration

The glomerular filtration rate is measured on narcotized dogs by determining inulin clearance according to a standard method of Fihr et al. (Klin.Wschr.33, 729 (1955)).

- Relaxation of blood vessels

The effect on vascular relaxation analogous to ANP is determined by a modified method of Faison et al. (Eur.

Pharmacol. 102, 169 (1984)). Rabbit thoracic grade is contracted by supramaximal concentration of serotonin. 15 minutes after the addition of the test substance, the serotonin-induced contractions were measured in comparison with the solvent control.

- 3roncholytic activity

According to Konzett and Sdssler (Arch.exper.Path,

Pharmacol. 195, 71 (1940)), antagonism of histamine bronchospasm after i.v. administration of the test substance.

Snasmolvtic efficacy on chicken rectum

According to the method of Currie et al. (Science, 221/4505, 71 (1F3) 1) was determined by contraction for the pasmolytic activity against carbohydrate.

Application of the compounds of the invention may be performed intravenously, subcutaneously, intramuscularly, intraoeritoneally, intranesally, by inhalation, transdermally, preferably by iontophoresis, or by known literature enhancers and orally. In animals of different species, there are doses which cause a significant drop in blood pressure (72 mm Hg) and / or diuresis (+ YOGA), respectively. saluresis (+ 300 µL) as well as an increase in hemstocrit (+3 X) with cyclic GA-PI + 20G / µL, between 1 µg / kg and 50 mg / kg. Doses for guinea pig broncholytic action are in the same range,

Binding to receptor γ cells from the glomerulosa zone of bovine 10-5 adrenal glands is achieved with IC 50. between 1.10 "and 1.10 *

minor. In vivo relaxation of the blood vessels on the aortic lychee rings is achieved with an εΟΟ θ between 1.10 and 1.1 O ⁴ mol / l. Concentrations ³ for spasmolytic action on chicken rectum are at equal doses.

Since each receptor binding compounds of the invention and Codl AIP in potency correlates well with ΐδ mecnsnisrnu biological effect is confirmed Ider * ^'1 effect between the natural peptides and compounds described herein. Therefore, other properties described for the biological properties of natural peptides not individually described herein can also be expected with the compounds of the invention.

and the potency of the compounds of the invention is. comparable to the effect of AI ?. An essential advantage of the compounds of the invention is their significantly smaller molecular size. It was not possible to conclude from the prior art that compounds with such a considerably smaller molecule size would exhibit efficacy in satisfactory valency. or derivatives of AI? higher molecular weight, similar to AIP.

The net utility of the compounds of the invention (especially in trandermal administration) is significantly greater than that of ANP and ANP-like derivatives. The compounds of the invention, unlike ANP, contain no disulfide bridges, thereby improving their metabolic stability against ANP and ANP-like derivatives.

The following compounds are particularly advantageous because their ANP-receptor binding value (see assay above -8 binding to ANP-receptors) is less than 3 x 10 mol.

pAuno-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly- J | pAca-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-11le-Gly- -Aca-Phe-Arg-Phe-D-Ala-Gly-Lys-Ile-Asp-Arg-Ile-Gly- -Ba a-Phe-Arg-Phe-D-Btu-Arg-Ile-Asp-Arg-11le-Gly- |

α-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-1le-Gly pPhe (4-NO 2) -Arg-Phe-D-Ala-Gly-Arg-Ile- Asp-Arg-11 le-Gly

-6A1 a-Phe-Arg-Phe-D-Ala-Gly-Arg-Met-Asp-Arg -1 le-GlypBAla-Cha-Arg-Cha-D-Ala-Gly-Arg -1 le-Asp-Arg - 1 le-Gly _r 3Ala-Phe (4-N02) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Gly-le 1

-46-BAla-Phe (4-NO 2) -Arg-Cha-D-Al and -Gly-Arg-11 le-Asp-Arg-11 le-Gly-, pQAla-Tyr-Arg-Cha-D-Ala- Gly-Arg-Ile-Asp-Arg-Ile-Gly-Bla-Tyr (Bzl) -Arg-Cha-D-Al and -Gly-Arg-Ile-Asp-Arg-Ile-Gly-,

-Apen-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-11le-Gly-, | -Abut-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile- Asp-Arg-Ile-Gly

-Gly-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-BA.1a-Phe-Arg -Phe ^ D ^ B tu-A rς-11e- As pA rg-1 e-GTy-i

-Bala-Phe-Arg-Phe-Pro-Gly-Arg-Ile-Asp-Arg-1le-Gly-t

-Ba a-Phe-Arg-Phe-D-Pro-Gly-Arg-Ile-Asp-Ar-gle le-Glyr-Tyr-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg -I le-Gly,? Tyr (Bzl) -Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly Phe _r -A rg-Tyr-D-Ala-Gly-Arg -I le-As.p-Arg-I le-Gly

-47- Ph-Arg-Tyr (Bzl) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

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

BAla-Phe-Arg-Ph-D-Ala-Gly-Arg-Nle-Asp-Arg-I-le-Gly

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

Aca-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-IleBla-Phe-Arg-Phe-D-Ala-Gly-Arg-11le-Asp-Arg-Ile

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

-48-Aca-D-Phe-Arg-Phe-D-Al-Gly-Arg-Ile-Asp-Arg-Ile-Aca-Cha-Arg-Phe-D-Ala-Gly-Arg-Ile- Asp-Arg-Ile

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

t -Bala-Phe-Arg-1

Αία -u χγ -rt i y

BAla-Phe (4-NO2) -Arg-Phe-D-Al and -Gly-Arg-Ile-Asp-Arg-Ile-, f-BAla-Phe-Lys-Cha-D-Al and -Gly-Arg -I le-Asp-Arg-Ile | -Bala-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-BAla-Tyr (Bzl) -Arg- Cha-D-Al and -Gly-Arg-Ile-Asp-Arg-Ile-Bla-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-1le -and

p.BAla-Phe-Ctr-Cha-D-Ala-Gly-'Arg-Tle-A-sp-Arg'-r''-.

pThc-Phe-Arg-Cha-D-Al and Gly-Arg-I le-Asp-Arg-Ile-Au-d-Arg-Phe-D-Al and-Gly-Arg-I le-Asp-Arg -I le-,

-49-Aund-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Phle-, -Aca-Arg-Phe-D-Al and -Gly-Lys-N le- Asp-Arg-I lepAca-Arg-Ser (Bzl) -D-Al-Gly-Lys-Nle-Asp-Arg-Ile-Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg -Ile-, | D-Btu-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Phe _r Aca-Arg-Phe-D-Ala-Gly-Arg-I Le- Gly-Arg-Ile-ix

... And 'A-Aca-Phe-Arg-Tyr (Me) -D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-r

-Aca-Phe-Arg-Phe-D-Ala-Gly-Arg-D-Ile-Asp-Arg-Ile -Aca-Phe-Arg-Phe-D-Ala7G ly-Arg-Ile-D-Asp- Arg-Ier-Aca-Phe-D-Arg-Phe-D-Al and Gly-Arg-Ile-Asp-Arg-Ile-Ac-D-Phe-Arg-Phe-D-Al and Gly -Arg-1 le-Asp-Arg -1 le-.

13A1 α-Phe-Arg-Phe-D-A1 α-Gly-Arg-Ile-Asp-D-Arg-Ile-.

_Γ ΒΛla-Phe-D-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-I Le-.

-50H-Lys-Arg-Phe-D-Ala

-Gly-Lys-N-Le-Asp-Arg-Ile- »

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

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

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

Z-Lys-Arg-Ph-D-Ala-Gly-Arg-Ile-Asp-Arg-Xleq

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

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

Menoc-Lv-Arg-Cha-C-Ala-Gly-Arg-Ile-Asp-Arg-le-i

H-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Lys-Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile (4-NO ₂₎ ) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-11le-Asp-Arg-Ile-Lys-Orn-Cha-D-Ala-Gly-Arg-11le-Asp-Arg-Ile-.

-51H-Lys-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile-.

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

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

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

·, Λ ^{! T} 'í

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

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

(-1-NOpz-Lys-Arg-Cha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile-j (4-NO ₂ ) Z-Lys-Orn-Cha-D-Ala-Gly- Arg-Ile-Asp-Arg-Ile— |

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

In view of the spectrum of activity, the compounds of the invention may be used as sntihypertensives, such as hypotensive agents, as diuretics, to improve blood flow (vasodilation activity), e.g., in vascular insufficiency and to treat cardiac insufficiency, coronary insufficiency, renal insufficiency, acute renal failure even in edema of any origin, e.g. cerebral edema, also in liver cirrhosis, as a spasmolytic for all smooth muscle organs, especially the stomach-intestinal tract, including bladder and urinary organs and broncholytics.

Furthermore, they can be used both for diagnosing the disease image and for testing the organ system. Therefore, they can; find use as adjuvants in the production and purification (affinity chromatography) of antibodies, respectively. in receptor preparations as well as in immunoassays (eg RIA, ELI3A) and receptor binding assays (eg radioreceptor assay) as specific and selective ligands.

The invention also relates to the use of the compounds of the formula I as medicaments with pharmaceutical preparations containing these compounds. Use in humans is preferred.

For parenteral administration, the compounds of the invention are optionally added with other conventional substances.

as solubilizers, emulsifiers or other excipients in a solution, suspension or emulsion. Suitable solvents are, for example: water, v

physiological saline or alcohols such as ethanol, propanediol or glycerin, sugar solutions such as glucose or mannitol eyes, or mixtures of various solvents

In addition, the compounds may be administered by implants, e.g., from a polylactide, a polyglycolide or a polyhydroxybutyric acid. Other application possibilities are intranasal administration, inhalation administration (piezo-meter, aerosol dispenser, powder inhaler), trandermal administration (lotions, creams, ointments, gels, passive patches, the efficacy of which may be enhanced by penetration enhancers and / or electric field (iontophoresis)), oral application (tablets, capsules, dragees, etc.).

The invention optionally includes the use of compounds of formula (I) as components and intermediates in the aforementioned biochemical, bioassays and immunological methods (antibody production, affinity chromatography, RIA, ELISA, radioreceptor assay).

The compounds of the invention can be produced by generally known methods in peptide chemistry. Such methods are described in Houben-Weyl, ethoden der organischen Chemie, Volume 15/2. Preferably, the production is carried out by solid phase synthesis of peptides (e.g. G. Sarany, R.3 Merrifield in The Peptides Analysis). Synthesis, Biology, Vol 2, 2-284 (i 980), Academic Press, New York, or RG Sheppard, Int.G.Pept. Res. 21,118 (1983)) or by other known methods. ^for the amino-protecting groups, those described in Kouben-weyl, et al., der der Organischen Chemie vol. _β 15/1 are used. Preferably, the urethane protecting groups are used.

groups such as fluorenylmethoxycarbonyl or a tert. butoxycarbonyl group. In order to prevent side reactions, the groups present in the amino acid side chains are usually additionally protected by suitable protecting groups (see, e.g., Houben-Vevl vol. 15/1 or

T. W. Green, Protective Groups in Crganic Synthesis).

In this case, Argv (CCl), Arg (di-S), Arg (Pmc), Arg (Mtr), Tyr (tBu), Tyr (Bzl), Tyr (2'-di-Cl-3zl), GerCtBu) are used. , Ger

?5Asp (t3u), Asp (3zl), Glu (t3u), Glu (tl), His (Tr), his (B), Lys (3oc ·), Lys (2), 2_Lys, QrnOoc), Dsp (3oc)) · Homo-Arg (III), Homo- Arg (PC), Home-Arg ().

Suitable polystyrene-based polyacrylamide-polyether resins are suitable for solid phase synthesis of compounds of formula (I). For the synthesis of cyclopeptides, it is desirable to use anchored groups which, upon cleavage, yield the peptide carboxylic acids. It is particularly advantageous to use such anchoring groups in which the cleavage is carried out under such mild conditions that any said impartial chain protecting groups remain. When using the Fmoc strategy, _λ are such anchored groups: the 2-methoxy-4-alkoxy benzyl alcohol group (T.Iergler et al., Proceedings. Of the American Peptide Symposium 1987, 5th Louise, p.

259 G.S. Kiarshall ed.Escom, Leiden (1968), hydroxyroxotrotonoylamidomethyl group (K. Kunz, E. Dombo, Aigew.Chem.Inf. Ld.Engl. 27,711 (1988)) or trialkoxybenzyl acrylic acid.

Jung, f-o-i -1.

P.Sieber, Peptides 1988, p

The cleavage of the amino protecting group is carried out in the case of the 3oc group with trifluoroacetic acid in dichloromethane or, in the case of the Fmoc group, preferably with an organic base, in particular amines such as piperidine or morpholine in LiF or N-methylpyrrolidone. Typical concentrations are 20 to 50% oasis in solvent, reaction times are between 10 and 120 minutes. Preferably, the cleavage is carried out in two steps, the first reaction time being about 1 minute. The resin is then briefly washed with solvent. A further cleavage of 203 with piperidine in ELF is carried out, then the solution is melted and the mixture is thawed with blur. Preferred solvents for these wash steps are 937, M 2, dichloromethane. trichloromethane, methanol, ethanol, issropropane, water and zeol in: ros ur

The removal of the piperidine is coupled to the Fmoc-amino acid required for further coupling. This cycle is repeated until the desired resin-bound peptide is formed.

Methods known in peptide chemistry may be used for coupling (see Kouben-Weyl, et al., Chemie Chemie, Vol. 15/2). Preferably, they use carbodiimides such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, ethyl (3-dimethylaminopropyl) carbodiimide, or O-benzotriazol-1-yl-tetramethyluronium hexafluprophosphate or tetrafluoroborate (R.Knorr et al., 1939, THL 30-39), THL 30-39) 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 _I-4 dihydrobenzotriazine (HOObt) optionally can promote racemisation or increase the reaction rate. The amino acids Asn and Gln are preferably coupled in the form of their N-protected p-nitrophenyl esters. The coupling is usually carried out with a 2- to 5-fold excess of the N-protected amino acid and the coupling reaction is carried out in a solvent such as dichloromethane, dimethylformamide, N-methylpyrrolidone (NMP) or mixtures thereof. The course of the coupling reaction is followed by an aiser assay (E. ^R. aiser et al., Anal. Biochem. 34, 595 (1970) or TNBS test).

In the case of incomplete acylation, the coupling is repeated until complete. Solid phase synthesis can be performed both manually and with the aid of a peptide synthesizer. .. ..

The peptides synthesized in this way are finally cyclized by suitable methods described in the literature as cyclizing agents, using the reagent used for amino acid coupling as well as pentafluorophenyl ester / DMAP or diphenylphosphorylaid (DPPA). For the synthesis of compounds of Formula 1, solid phase synthesis according to the Fmoc strategy using the anchored 2-methoxybenzyloxybenzyl ester group is preferred. ^{For the} construction of sequences, DCC / HOBt-, DIC / HOBt- or TSTU-methods are suitable. After construction of the sequences on the resin, the N-terminal Fmoc group is cleaved in the usual manner, the resin is washed thoroughly with dichloroethane after removal of the piperidine and then treated with a 1% trifluoroacetic acid solution to cleave the peptide. In this case, the side chain protecting groups of the peptide are retained. After distilling off the solvent, the peptides are reacted with a cyclizing agent, preferably diphenylphosphoryl azide, to the corresponding cyclopeptides. Thereafter, said side chain protecting groups are removed with the corresponding cleaving agent. Preferred are mixtures of trifluoroacetic acid / scavenger. Substances such as anisole, thioanisole, cresol, thiocresol, ethanedithiol, water or the like and mixtures thereof are used as scavengers. The peptides are then treated by conventional methods in peptide chemistry and purified.

Purification of the crude products obtained is carried out by gel chromatography, for example on Sephadex U25 ΐ (MR 1400) or Gl 5 (MR 1400) with 1% or 5% acetic acid, if necessary further purification by preparative HP-HPLC with methanol · acetonitrile / water gradients with the addition of 1 to 2% trifluoroacetic acid.

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

Purification is preferably performed by reverse phase HPLC using water / acetonitrile gradients with the addition of 0.1 to 0.2% trifluoroacetic acid.

The purity of the compounds of formula (i) was tested by RP-HPLC. Amino acid analysis is performed on an ion exchange resin (LKB) and by gas chromatography on a chiral column for additional control of racemization. From this, both the C-NMR spectra (Bruker 400 MHz) and the FAB-Jot spectrum (Finnigan MAT 90) are recorded. Sequence determination is performed by gas phase sequencing after tryptic cleavage.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

p-Ala-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Agp-Arg-Ile-Gly '

Peptide synthesis was performed on an Advanced CheaTech ACT200 peptide synthesizer using a Paoc-strategy using a modified control program. A 50 ml shake reactor was charged with 1 g of 2-methoxybenzyl ester resin from Fachem, Switzerland, which was

0.5 mmol of Fmoc-glycine to this cycle. The following amino acid derivatives are used: Faocr-Ile-OH, -Fmoc-Arg (Mtr) -OH, Fmoc-Asptt 3 -OH, Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc-Phe-OH and Fmoc - / $ Ala-OH. Coupling is performed with 3 equivalents each of Fmoc amino acid, 1-hydroxybenzotriazole and dicyclohexylcarbodiimide (coupling time 40 minutes). After execution

In the TNBS assay, in the case of incomplete acylation, the coupling is repeated using the same reagents and excess. Upon complete acylation, another synthesis cycle is started. The cleavage of the Faocoprotecting groups is. always with 2Q3 & piperidine in DMF

-59 (once 3 minutes, once 15 minutes). Between reactions, the resin was washed 1 time each with 1 time DMF. After the construction of the Η- β Ais-Phe-Arg (Mtr) -Phe-D-Ala-Gly-Arg (Mtr) -Ile-Asp (tBu) Arg (Mtr) -Ile-Gly- sequence on the polymeric support, the resin is thoroughly washed ³ di chl Orme Thane: and thereafter 5 times with 20 ml of 1% solution of trifluoroacetic acid in dichloromethane at room temperature for a maximum of 10 minutes Ppending intense lilac tint resin) fioztoky were combined and evaporated in vacuo, the residue is triturated with ether, the ether was decant, the peptide was dried under a stream of nitrogen and taken up in 130 ml of DMF having a pH adjusted to about 8.5 with triethylamine, the solution was cooled to -20 ° C and 0.2 g (G, Y5 mmol) of diphenylphosphoryl azide was added. The mixture was allowed to stand at -20 ° C for 48 hours, at 4 ° C for 48 hours. The pH is maintained at 8.5 with triethylamine. The DMF was then removed in vacuo, the residue was triturated twice with ether, the ether was decanted and the residue was dried under a stream of nitrogen. The side chain protecting groups are removed with trifluoroacetic acid / anisole (90/10) at room temperature for 24 hours. The solution was evaporated in vacuo, the residue 3e digested? with ether and dried. The crude peptide was purified over a Dynamax C18, 3 / um-column (10 x 2.14 ca) using gradients A: water / acetonitrile trifluoroacetic acid 95/5 / 0.2 and Bi dtto 20/80 / 0.2 from 10% B to 80% B in 11 minutes, flow rate 20 ml, tattoo time 6 _f 0i minutes. After freeze-drying, an amorphous colorless powder is obtained. FAB-MS (M + H) &lt; + &gt;

Example 2

- Aind-βe-Apg-Phe-D-Ala-Gly-Arg-He-Agp-Arg-He-Gly2 and using Faoc-Aind-OH instead of Fmoc-Ala Ala-OH to obtain the crude peptide as described in Example 1, who

Purify under chromatography conditions described (52-80% B in 11 min, retention time 7.45 min).

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

Example 3

Ac-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Agp-Arg-He-Gly ^

2a using Fmoc-Aca-OH instead of Pmoc- / Ala Ala-OH gave the crude peptide according to Example 1 which was purified using the conditions indicated for chromatography (5% to 80% B in 11 min, chain time 6.00 min ). FAB-1α (M + H) + - 1403.1

Example 4

-Aca-Phe-Arg-Phe-D-Ala-Gly-Lys> Il-Asp-Arg-lle-Gly η

2a using Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH instead of Faoc-β-Ala-OH gave the crude peptide according to Example 1, which was purified by chromatography under the conditions described (5% to 80% B in 11 min) , retention time 5.80 min). FAB-MS (M + H) + -1374.9

Example 5 -Ala-Fhe-Arg-Phe-D-Stu-Arg-Ile-Asp-Arg-Ile-4-Gly2 and using Fmoc-D-3tu-OH instead of Fmoc-D-Ala-OH to obtain the crude peptide as described in of Example 1, which is purified by chromatography under the conditions described

-61 (5% to 80% B in 11 min, retention time 6.05 min).

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

Example &

- (4-NO 2) -Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly η

2a using Faoc-Phe (4NO2) -OH and without Fmoc- β Ala-OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (596 to 80% B in 11 min, retention time 6.45) min).

FAB-MS (M + H) &lt; + &gt; = 1334.9

Example 7 * '

- .beta.alpha.-Al-Phe-Arg-Phe-D-Ala-Gly-Arg- .alpha.-Asp-Arg-Ile-GlyZa, using the addition of Faoc-.alpha.-OH, following the procedure described in Example 1, a crude peptide is obtained. Purify by chromatography under the conditions described * (5% to 80% B in 11 min, retention time 6.10 min).

FAB-MS (M + H) &lt; + &gt; with 1378.8

Example 8? Ala-Cha-Arg-Oha-D-ALa-Gly-Arg-lig-Asp-Arg-11le-GlyZa Using Fmoc-0ha-OH instead of Fmoc-Phe-OH, the crude peptide was obtained as described in Example 1 The residue was purified by chromatography under the conditions described (5% to 80% Bzall min, retention time 7.75 min).

FAB-MS (M + H) &lt; + &gt; - 1373.0

-62Example 9

- β Al a- Phe (4 - Ν 2 O) -Arg-Phe-D-Al a- ^G capable of associating Arg-11 e - Ag II p e- Gly2 Arg- Arg-Phe (4-NO2) to following the procedure described in Example 1 gave the crude peptide which was purified by chromatography under the conditions described (5% to 80% in 11 min, retention time 6.50 min).

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

Example 10

? Ala-Phe (4-NO 2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Tle-Gly2 and using Fmoc-Cha-OH; and Fmoc.-Phe (4-NO 2) -OH instead of Fmoc.-Phe-OH gave the crude peptide as described in Example 1 and purified by chromatography under the conditions described (5% to 80% · B in 11 min, retention time). 7.40 min) ·

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

Example 11

- Ala-Tyr-Arg-Cha-T-Als-Gly-Arg-Tl-Ayp-Arg-Ile-GlyZ using Fmoc-Tyr (tBu) -OH and Fmoc-Cha-OH instead

FmooPhe-OH gave the crude peptide as described in Example 1 and was purified by chromatography under the conditions described (5% to 80% in 11 min, retention time 6.40 min).

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

-63Example 12

- β Ala-Tyr (Bzl) -Arg-Cha-D-Al & -Gly-Arg-Ile-Asp-Arg-Ile-Gly2 using Faoc-Tyr (Bzl) -OH and Fmoc-Cha-QH with the procedure described in the example 1 gives the crude peptide which is purified by chromatography under the conditions described (5% to 80% in 11 min, retention time 8.50 min).

FAB-MS (MH &lt; + &gt;) = 1473.2

Example 13, Aca-Phe-Arg-Phe-β Ala-Arg-Ile-Agp-Arg-Ile-Glyq

2a using Faoo Aca-OH 'and Faoc- / Ala-OH, the crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (20% to 80% in 10 min, retention time 4.60 min) ).

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

Example 14

- Aca-Phe-Arg-Phe-Abut-Arg-Ile-Asp-Arg-Ile-Gly2 and using Fmoc-Aca-OH instead of Faoc - /} Ala-OH and

The crude peptide was prepared by Fmoc-Abut-0H as described in Example 1 and purified by chromatography under the conditions described (20% to 80% 3 for 10 min, retention time).

4.85).

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

Example 64 r-Apen-Phe-arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly

pea as described in Example 1 yields the crude peptide which is purified by chromatography under the conditions described (20% to 80% B in 10 min, retention time 4.50 min).

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

EXAMPLE 16 .but-Phe-4g-Phe-D-Ala-Gly-Arg-1-l-ep-Arg-Ile-Gly-.

2a using Faoc-Abut-OH instead of Fmoc-β-α-OH a crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (20% to 80% B in 10 min, retention time 4.35 min) ).

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

Example 17

-Gly-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-4-sp-Arg-He-Gly-j

Using Fmoc-Gly-OH instead of Fmoc-β Ala-QH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (20%

80% B in 10 min, retention time 4.45 min).

FAB-31S (1 H + H) + = 1346.8

-65Example 18

Using the α1-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly2a used in Example 1 of the described Fmoc-amino acids, a crude peptide is obtained which is purified under the conditions described for chromatography (20% 80% B in 10 min, retention time 3.25 min).

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

Example 19

Ac α -Arg-Phe-D-Al α -Gly-Arg-Ile-Agp-Apg-Ile-Gly ε and using Fmoc-Aca-OH instead of Fmoc-> Ala-OH was obtained as described in Example 1 crude peptide which was purified by chromatography under the conditions described (20% to * 80% B in 10 min, retention time 3.45 min).

FAB-MS (M) &lt; + &gt; = 1255.8

Example 20 Aind-Arg-Phe-D-Al-β-Gly-Arg-Ile-Asp-Arg-Ile-Gly2a Using Fmoc-Aund-OH Instead of Faoc-? Ala-OH with the Method Described in Example 1 The crude product was purified by chromatography under the conditions described (20% to 80% B in 10 min, retention time 5.15 min).

FA.MS (2d + H) + = 1325.8

-66Example 21

Aca-Phe-Arg-Phe-Aoc- -Arg-Ile-Asp-Arg-Ile-Gly-i

Using Fmoc-Aca-OH instead of Faoc- / Ala Ala-OH and Fmoc-Aoc-QH, the crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (5% no. Θθ% in 11 min, retention time 7.10 min).

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

Example 22

β-Ala-Phe-Arg-Phe-D-Ala-Gly-Arg-Aib-Asp-Arg-Ile-Gly-;

Using additional Fmoc-Aib-OH, the crude peptide was purified as described in Example 1 and purified by chromatography under the conditions described (5% at 80 ° S in 11 min, retention time 5.70 min).

FAB-1S (M + H) + = 1217.6

Example 23

- {Ala-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Aib-Arg-Ile-Gly-. ..

Using Fmoc-Aib-OH instead of Fmoc-Asp (tBu) -QH, the crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (35% to 65% in 13.5 min, retention time 3.70). min).

FA3-MS (M + H) &lt; + &gt; = 1330.9

-67Example 24

- Ala-Phe-Arg-Phe-L-Btm-Arg-Ile-Asp-Arg-Ile-Gly2 and using Fmoc-L-Btii-OH instead of Fmoc-D-Ala-OH the crude peptide was prepared as described in Example 1. which was purified by chromatography under the conditions described (5% to 80% B in 11 ml, retention time 5.90 min).

FAB-MS (54 + H) &lt; + &gt; = 1372.7

Example 25

? Ala-Phe-Arg-Phe-D-Btm-Arg-Ile-Asp-Arg-Ile-Gly-.

Using Fmoc-D-Btm-OH instead of Fmoc-D-Ala-OH, the crude peptide was purified as described in Example 1 and purified by chromatography under the conditions described (5% to 80% in 11 min, retention time 6.05 min). ).

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

Example 26

Ala-Phe-Arg-Phe-Pro-Gly-Arg-Ile-Asp-Arg-Ile-Gly, and ^by using Fmoc-Pro-OH instead of Fmoc-D-Ala-OH as described in Example 1 gave crude peptide was purified by chromatography under the conditions described (5% to 80% in 11 min, retention time 6.15 min).

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

-68Example 27

- β Ά a-Phe-Arg-Phe-B-Pro-Gly-Ag-11 e-Agp-Arg-II e-Gly

2a using Fmoc-D-Pro-OH and instead of Fapc-D-Ala-QH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.35). min).

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

EXAMPLE 28 Tyr-Apg-Phe-D-Ala-Gly-Arg-Ile-sp-Arg-Ile-Gly

In addition to the use of Fmoc-Tyr (tBu) -OH and without Fmoc-β ALe-QH, the crude peptide is obtained as described in Example i and purified by chromatography using

--------- conditions described 5% to 80% B in 11 min; "Retention time"

5.40 min).

FAB-MS (M + H) &lt; + &gt; = 1306.0

Example 29

-Tyr (Bzl) - Arg-Phe-D-Ala-Gly-Arg-Ile-Agp-Arg-Ile-Gly-n

In addition to the use of Fmoc-Tyr (Bzl) -OH and without Fmoc-γ-a-OH, the crude peptide was obtained as described in Example 1 and purified using chromatography under the conditions described (5% to 80% B in 11 min, retention). time 6.10 min).

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

-69Example 30

-Phe-Arg-Tyr-D-Ala-Gly-Arg-Ile-Aap-Arg-Ile-GlyZa with the additional use of Faoc-Tyr (tSu) -OH and without Faoc-Ala AlaOH, the crude peptide was obtained as described in Example 1, Purify according to the described chromatography conditions (5% to 80% B in 11 min, retention time 6.55 min).

FAB-MS (M + H) &lt; + &gt; = 1305.9

Example 31

-Phe-Arg-Tyr (Bzl) -D-Ala-Gly-Arg-Tle-Agp-Arg-He-Gly For additional use of Faoc-Tyr (Bzl) -OH and without &

Fmoc-Ala Ala-OH was obtained as described in Example 13 of the crude peptide, which was purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time).

7.10 min).

FAB-MS (M + H) + = 1395.9

Example 12

- 3 Ala-Phe-Arg-Phe-H-Clg-Arg-Tle-Agp-Arg-Tle-Gly-

L__ϊ

Using Fmoc-L-Cig-QH instead of Fmoc-D-Ala-OH gave the crude peptide as described in Example 1 and purified by chromatography under the conditions described (5%

80% in 11 min, retention time 6.90 min).

FAB-MS (M + H) + = 1400.8-70Example 33

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

The addition of Fmoc-Nle-OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% ‘to 80% in 11 min, retention time 6.40 min).

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

Example 34

- /} A1 and -Ph-Arg-Cha-D-Ala-Gly-Arg-Met-Agp-Arg-Il

Peptide synthesis was performed on an ACT200 peptide synthesizer from Advanced ChemTech using a Fmoe strategy using a modified control program. A 50 ml shaking reactor was charged with 1 g of 2-methoxybenzyl ester resin from Achem, Switzerland, which was charged with a 0.5 mmol cycle of Fmoc-isoleucine. The following amino acid derivatives were used: Fmoo-Arg (TM) -H, Fmoc-Agp (tBu) -OH, Fmoc-Met-OH, Fmoc-Giy-OH, Fmoc-D-Ala-OH, Fmoe-Cha-OH, Fmoc- Phe-ΟΙΓ and Fmoc - ^ Ala-OH. Couplings were performed using 3 equivalents of Fmoc-amino acid, 1-hydroxybenzotriazole and dicyclohexylcarbodiimide (coupling time 40 minutes). Following the TNBS assay, coupling incomplete acylation is repeated using the same reagents and excess. Upon complete acylation, the next cycle of synthesis is started. Cleavage of the Fmoc-protecting groups is carried out with 20% piperidine in DMF (once 3 minutes, once 15 minutes). Between reactions, the resin was washed with 10 times DMF. After the construction of the linear sequence of H- / cAls-Phe-Apg (Mtr) -Cha-D-Ala-Gly-Arg (Mtr) .gamma.-Agp (tBu) -Arg (Mtr) -He on a polymeric support, it was prysed.

The resin was washed thoroughly with dichloromethane and then treated 5 times with 20 L of a 1% solution; of trifluoroacetic acid in dichloromethane for a maximum of 10 minutes at room temperature (until intense IIIa of resin color).

The solutions are combined and distilled off under vacuum, the residue is triturated with ether, the ether is decanted off, the peptide is dried in nitrogen production and taken up in 130 ml of DMF, the pH is adjusted to about 8.5 with triethylamine, the solution is cooled to -20 ° C and 0.2 g (0.75 mmol) of diphenylphosphoryl azide are added. Leave to stand at -20 ° C for 48 hours, at 4 ° C for 48 hours. The pH is maintained at 8.5 with triethylamine. The DMF was then removed in vacuo, the residue was triturated twice with ether, the ether was decanted and the residue dried with a stream of nitrogen. The side chain protecting groups are cleaved with trifluoroacetic acid / anisole (90/10) in 24 hours. The solution is concentrated in vacuo, the residue is digested with ether and dried. The crude peptide was purified through a Dynanax C18, µm-column (10 x 2.15 ca) 2a using gradients A: water / acetonitrile / trifluoroacetic acid 95/5 / 0.2 and B: dtto 20/80 / 0.2 z 5% B to 80% B in 11 minutes, flow rate 20 ml, Tat time 7 ^ 80 min. After freeze-drying, an amorphous colorless powder is obtained.

FA 3-MS (M + H) + = 1327.9

Example 35

- / 3Ala - Arg - Phe - D - AL - Gly - Arg - Ue - Asp - Arg - ηβη

Using Fmoc-He-OH instead of Fmoc-4-et-OH and without Faoc-Cha-OH, the procedure described in Example 1 gave the crude peptide, which was purified by chromatography under the conditions described (20% to 80% B in 10 min, retention). time 3.25 min).

FAB-MS (M + H) &lt; + &gt; = 1156.7.

-72Example 36

Aca-Apg-Phe-D-Ala-Gly-Arg-Ile-Asp-Ile2a using Fmoc-As α-OH ais to Fmoc-^ ALa-OH and Paoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc -Cha-OH was prepared according to the procedure described in Example 1, which was purified by chromatography under the conditions described (20%; aia 80% B in 10 min, retention time 3.70 min).

FAB-MS (M + H) &lt; + &gt; = 1198.8

Example 37

Aand-Arg-Phe-H-Al and -Gly-Arg-He-Asp-Arg-Ile2a using Faoc-Aund-OH instead of Fmoc- / 3 Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, the crude peptide was prepared as described in Example 1 and purified by chromatography under conditions B described (20% ca 80% B in 10 min, retention time 5.55 min).

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

Example 38 ρ Ae α-Phe-Arg-Phe-D-Al α-Gly-Arg-Ile-Agp-Arg-Ile

2a using Fmoc-Aca-QH instead of Fmoc-?l Ale-OH and Fmoc-Ile

OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, a crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (20% to 80% B · 10 min, retention time 4.90 min) .

FAB-MS (M + H) &lt; + &gt; = 1346.2

-73Example 39

- Λ Ala-Phe-Arg-Phe-D-Al and -Gly-Arg-Ile-Asp-Arg-He?

Use of Fmoc-Ile-OH instead of Fmoc-Met-OH and bea

Fmoc-Cha-OH was prepared as described in Example 1, crude peptide, which was purified by chromatography using the conditions described (20% and with 80% B in 10 min, retention time 4.50 min) »

FAB-MS (M + H) &lt; + &gt; = 1304.0

Example 40 i-P? Ala-Phe? Arg-Phe-D-Ala-Gly-Lys-Nle-Agp-Arg-Ile2a using Fmoc * -Lys (BOC) -OH and Fmoc-Nle-OH instead of Fmoc-Me t-OH. and without Fmoc-Cha-OK, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5% 80% &lt; min &gt;, reaction time 6.10 min).

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

Example 41 i-ALs-Phe-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-II e2a additional use of Fmoc-lys (BOC) -OH and Fmoc-Ser (Bzl) -0H instead of Fmoc-Cha-OH and Fmoc-Nle-OH instead of Fmoc-Met-OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5% to 80% B in 10 min, retention time 6, -20 min).

FAB-MS (M + H) &lt; + &gt; = 1305.0

-74Example 42

- Ac α-Phe-Lys-Phe-D-Al α-Gly-Arg-Ile-Asp-Arg-Il

"and

Using Fmoc-Aca-OH instead of Fmoc- / 9 Ala-OH and Faoc-He-OH instead of Faoc-Met-OH and Fmoc-Lys (BOC) -OH without Fmoc-Cha-OH gave the crude procedure as described in Example 1. peptide purified by chromatography under the conditions described: (5% ^to 80% B in 11 min, retention time 6.60 min).

FAB-MS (M + H) &lt; + &gt; = 1318.2,.

Example 43

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

Using additional Fmoc-Lys (BOC) -OH and Fmoa-Aca-OH instead of Fmoc-Ala-OH and Faoc-Ile-OH instead of Faoc-Met-OH and without Fmoc-Oha-OH 'were obtained as described in Example 1 crude peptide which was purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.40).

FAB-MS (M + H) &lt; + &gt; = 1290.2

Example 44 Aa-Phe-Arg-Cha-D-Al a-Gly-Arg-Ile-Aep-Arg-Ile-r

Using Fmoc-Aca-OH instead of Fmoc- / ^ Ala-OH a

Fmoc-Ile-OH instead of Fooc-Met-OH gave the crude peptide as described in Example 1, which was purified using chromatography under the conditions described (5% to 80% B in 11 min, retention time 7.35 min).

-75 FAB-MS (M + H) &lt; + &gt; = 1352.2

Example 45

-Aca-D-Phe-Arg-Phe-D-Ala-Gly-g-Ile-Asp-Arg-HeZa using Fmoe-Aca-OH instead of Fmoc-Z ^ Ala-OH and Fmoc-He-OH instead of Fmoc- itfet-ΟίΓ and Fmoc-D-PheOH and without Pmoc-Cha-OIT gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5 $ n & 80 $ B in 11 min) (retention time 6). , 35 min) *

FAB-MS (M + H) &lt; + &gt; = 1346.2

Example 4d p Ac α-Gha-Arg-Phe> D-Al α-Gly-Arg-Ile-Agp-Arg> HeZa using Faoc-Aca-OH instead of Fmoc; - 3Ala-OH and Fmoc-Ile-OH instead of Faoc -Met-ΟΙΓ with the procedure described in? Example 1 yields a crude peptide which is purified by chromatography under the conditions described ($ 5 to $ 80 B in 11 min, retention time 7.35 min).

FAB-MS (M + H) &lt; + &gt; = 1352.0

Example 47

Ala-Phe-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile Using Faoc-He-OH instead of Fmoc-Met-OH, the crude peptide was obtained as described in Example 1, which was

-76čistí chromatography conditions described (5%. _K g

Szall min, retention time 5.90 min).

FAB-MS (M + H) &lt; + &gt; = 1309.5

Example 48 µ Al α- (4NO 2) Phe-Arg-Phe-D-Ala-Gly-Arg-He-Asp-Arg-Ile For additional use of Fmoc- (4-NO 2) Phe-OH and Fmoc-Ile 4 OH instead of Fmoc Met-OH and without Fmoc-Cha-OH gave the desired crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B in 10 min, retention time 6.85 min).

FAB-MS (M + H) &lt; + &gt; = 1348.9

EXAMPLE 49 [alpha] -Pha-Lys-Cha-D-Al [alpha] -Gly-Arg-Ile-Ag [beta] -Ar-Ile for Additional Use of Fmoc-Lys (SOC) -OH and Fmoc-Ile-OH Instead of Fmoc- Met-OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% 80% B in 10 min, retention time 6.75 min).

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

-77Example 50

Clg-Arg-Cha-D-Ala-Gly-Arg-He-Agp-Arg-Tle

Using Faoc-Clg-QH instead of Fsoe - / - Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Phe-OH, the crude peptide was obtained as described in Example 1, which was purified by chromatography under the conditions described (5% 80% B in 11 min, retention time 7.35 min).

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

Example 51

- ^ Ala- (4NO2) Phe-Arg-Cha-D-Al and -Gly-Arg-Ile-Agp-Arg-Iles Using Fmoc- (4-K02) Phe-OH instead of Fmoc-Phe-OH and Fmoc-Ile -OH instead of Fmoc-Met-OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% _n and B in 10 min, retention time 6.50 min).

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

Example 52

- β Al α-Tyr (bzl) - Arg-Ch α-D-Al α-Gly-Arg-IX®-Asp-Arg-Ile?

Using Fmoc-Tyr (Bzl) -OH instead of Fmoc-Phe-OH and Fmoc-He-QH instead of Fmoc-Met-OH gave the crude peptide as described in Example 1 and purified by chromatography-78 under the conditions described (5%). fta θθ% B in 10 min, retention time 8.20 min).

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

Ί

Example 53

- ALa-Tyr-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-11e Using Fmoc-Tyr- (tBu) -OH instead of Faoc-Phe-OH and Faoc-Ile-OH instead of Fmoc- Met-OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% _to 80% B in 10 min, retention time 6.45 min).

FAB-MS (M + H) &lt; + &gt; = 1325.8

Example 54 The Arg-Ch-D-AL-Gly-Arg-He-Asp-Arg-Tle Using Fmoc-THc-OH instead of Fmoc-Als-OH and Faoc-Ile -OH instead of Fmoc-itfet -OH and without Fmoc-Phe-OH were progressed; as described in Example 1 yields the crude peptide? which is purified by chromstography under the conditions described (5% to 80% 3 in 10 min, retention time 6.45 min).

FAB-MS (M + H) &lt; + &gt; = 1279.7

-79Example 55

- βΆ. α-Phe-Ctr-Cha- D-Ala-Gly-Arg-He-Agp-Arg-Ile For the additional use of Fmoc-Ctr-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH was prepared as described in Example 1 crude peptide which is purified by chromatography under the conditions described (5% to 80% B in 10 min, retention time 7.00 min).

FAB-MS (M + H) &lt; + &gt; = 1310.6

Example 56 = The -Phe-Arg-Gh and D-Ala-Gly-Arg-Ile-Aap-Arg-Ile Using Fmoc-Thc-OH instead of Fmoc- / ¾ Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met- OH gave crude peptides as described in Example ~ 1- which was purified by chromatography under the conditions described (5% η · β 80% B. in 10 min, retention time 7.60 min).

FAB-MS (M + H) &lt; + &gt; = 1426.7 [deg.]

Example 57

- Gig-Apg-Cha-D-Al and -Gly-Agg-Ile-Asp-ApgLlle Using Fmoe-Clg-OH instead of Fmoc- / Ala Ala-OH and Fmoc-He-OH instead of Fmoc-Met-OH and without Emoc -Phe-OH yielded the crude peptide as described in Example 1, which was recovered

-80 purified by chromatography under the conditions described (5% to <80% B in 10 min, retention time 8.90 min).

FAB-MS (M + H) &lt; + &gt; and 1406.7

Example 58

- Aza-arg-Phe-D-ALa-Gly-Lys-Nle-Asp-Arg-Ileη

2a the additional use of Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH instead of Fmoc-β ALa-OH and Fmoc-Nle-OH instead. Fmoe-Met> OH and without Fmoc-Cha-OH 'as described in Example 1 gave the crude peptide, which was purified by chromatography under the conditions described (5% to 10% B in 11 min, retention time 5.45 min) .

FAB-MS (M + H) &lt; + &gt; = 1170.6

Example! 59

- Aca-Ag-Ser (Bzl) -D-Aia-Gly-Lys-Nle-Asp-Arg-He-i

Using Fmoc-Aea-OH instead of Fmoe- / 3Ala-OH, Fmoc-Nle-OH instead of Fmoc-Met-QH and Fmoc-Sea? (Bzl) -OH instead of Fmoc-Cha-OH gave crude as described in Example 1. peptide purified by chromatography under the conditions described (5% to 80% B for 11 min ^; retention time 5.70 min). FAB-MS (M) &lt; + &gt; = 1200.5

-81Example 60

Ac α-Phe-Arg-Phe-D-Al α-Gly-Lys-Nle-Arg-IleZa additional use of Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH instead of Fmoc-Ala-OH and Fmoc- Instead of Fmoc-4-et-OH-α without Fmoc-Cha-OH and Fmoc-Asp (tBu) -OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5% to 80%). B in 11 min, retention time 7.10 min).

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

Example 6l

Ala-Phe-Arg-Phe-D-Al and -Gly-Lys-Nle-Arg-Ile Using Fmoc-Lys (BOC) -OH and Fmoc-Nle-OH instead of Fmoc-Met-OH without Fmoc-Cha- OH and Fmoc-Asp (tBu) -OH as described in Example 1 gave the crude peptide, purified by chromatography under the conditions described (5% a and 80% 3 in 11 min, retention time 6.90).

FAB-MS (M + H) &lt; + &gt; = 11 $ 0.6

Example 62

From Ac α-Arg-Phe-D-A1 α-Gly-Lys-Nle-Arg-He->

Using Fmoc-Lys (BOC) -OH and Fmoc-Aca-OH in place of Fmoc-Ala-OH and Fmoc-Nle-OH instead of Fmoc-4-et-OH and without Fmoc-Cha-OH yielded crude by the procedure of Example 1. peptide which is purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 5.95 min). FAB-MS (M + H) &lt; + &gt; = 1055.7

-82Example 63

Al? -Ag-Phe-D-Al? -Gly-lys-Nle-Arg-Ile.

2a using Fmoc-Lys (BOC) -OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-Asp (tBu) -OH, the crude peptide was obtained according to Example 1, which was purified by chromatography under the conditions described (5% per B per min, retention time 5.90).

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

Example 64 r-AL α-Phe-Gly-Ser (Bzl) -D-A1 α-Gly-Lys-Nle-Asp-Arg-He->

Using Fmoc-Lys (BOC) -OH and Fmoc-Ser (Bzl) -OH and Fmoc-Nle-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, the crude peptide was purified according to Example 1, which was purified Chromatography under the conditions described (5% and 80%)

B over 11 min, retention time 6.85 min).

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

Example 65 *

p Ac α-Phe-Gly-Phe-D-AL α-γ-Lys-Nle-Asp-Apg-Ile-,

2a using Fmoc-Aca-QH instead of Fmoc- / bAla-OH and Fmoc-Nle-OH instead of Fmoc-Met-QH and Fmoc-Lys (BOC) -OH and without Fmoc-Cha-OH, the crude peptide was obtained according to Example 1 which is purified by chromatography as described in

-83min (5% to ⁸ P% B in 11 min, retention time 7.40 min). FAB-MS (M + H) &lt; + &gt; = 1248.5

Example 66

- Ala-Gly-SerBzO-B-Ala-Gly-Lys-Nle-Agp-Arg-HeZ using Fmoc-Lys (BOC) -OH and Fmoc-Ser (Bzl) -0H instead of Fmoc-Phe-OH and Fmoc -Nle-OH instead of Fmoc-4-et-QH and without Fmcc-Chn-OH was followed by the procedure of Example. 1 gives the crude peptide, which is purified by chromatography using the conditions described above (5% to 80% B in 11 min, retention time 5.80 min).

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

Example 67

- and Ac-Gly-3 _e r (Bzl) -D-Ala-Gly-Lys-Nle-Asp-Arg-Ile * i · ΌZa using Fmoc-Aca-OH instead of Fmoc- / 3Ala-OH, Fmoc -Ser (Bzl) -OH instead of Fmoc-Cha- and Fmoc-Nle-OH instead of Fmoc-Met-OH was prepared according to the procedure of Example 1 crude peptide, which was purified by chromatography under the conditions described (5% to 80% B in 11 min) Retention Time 6.20 min).

FA3-MS (M + H) + = 1101.5 —84—

Example 68

- β Ala-Ser (Bzl) -D- Ala-Gly-Iy s-Nle-Agp-Arg-Ile2a using Fmoc-Ser (Bzl) -OH instead of Fmoc-Cha-OH and Fmoc-Ile-OH instead of Fmoc-Met -OH and addition of Fmoc-Lys (BOC) -OH was prepared as described in Example 1 to give a crude peptide which was purified by chromatography under the conditions described (5% ^to 80% Bv in 11 min, retention time. 6.05 min). FAB-MS (M + H) &lt; + &gt; = 1002.6

Example 69

Ac α-Ser (Bzl) -D-Ala-Gly-lys-Nle-Asp-Arg-Ile2q use. Fmoc: -Aca-GH site Fmoc- / J Ala-QH, Fmoc-Ile-OH sites Fmoc-Met-OH and Fmoc-Ser (Bzl) -0H sites © Fmoc-Cha-OH and Fmoc-Lys (BOC) - OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% to θθ% B in 11 min, retention time 6.60 min).

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

Example 70

Btu-Apg-Phe-D-Al and Gly-Arg-Ile-Asp-Arg-Ile-i

2a using Fmoc-Btu-OH in place of Fmoc -? Ala-OH and

Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH was prepared as described in Example 1, crude peptide, which was purified by chromatography under the conditions described QG5S B

2a 11 min, retention time 5.34 min).

FAB-MS (M + H) &lt; + &gt; = 1225.6

-85Example 71

0-3 tu-Arg-Phe-D-Al and -Gly-Arg-Ile> Agp-Arg-Ile-.

Using Fmoc-D-Stu-OH instead of Fmoc-β Ala-OH and Fmoc-Ile-OH instead of Fmoc-Meth-OH and without Fmoc-Cha-OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described. (5% to 80% B in 11 min, retention time 5.15 min).

FAB-MS (M + H) &lt; + &gt; = 1225.6

Example 72

- β Ala-Arg-Phe-D-AL and -Gly-Arg-Ile-4 * ^ - II βη

Using Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH and Fmoc-Asp (tBu) -OH 3e as described in Example 1, the crude peptide was purified and purified. (5% to 80% B in 11 min, Retention Time 6.15 min).

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

Example 73 j-Ac a-Arg-Phe-D-Al α-Gly-Arg-Ile-Arg-HeZ using Fmoa-Aca-OH instead of Fmoc- / Ala-OH and Fmoc-He-OH instead of Fmoc-Met- OH and without; Fmoc-Cha-OH and Fmoc.-Asp (tBu) were prepared as described in Example 1, crude peptide, which was purified by chromatography under the conditions described (5% and 80% B in 11 min, retention time 6.10 min).

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

-86Example 74

- Ac α-Phe-Arg-Phe-D-Al α-Gly-Apg-Ile-Gly-Arg-II using Fmoc.-Aca-OH instead of Fmoc- / 3 Ala-OH, Fmoc-Ile-OH instead of Fmoc -Met-OH and Fmoc-Gly-OH instead of Fmoc.-Asp (tBu) -OH and without Fmoc-Cha-OH yield the crude peptide as described in Example 1, which is purified by chromatography under the conditions described (5% to θθ% Bzall min, retention time 5.80 min).

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

Example 75

- Ac-Phe-Arg-Tyr (OMe) -D-Al-Gly-Arg-Ile-Agp-Arg-Ile-

Using Fmoc-Tyr (OMe) -OH and Fmoc-Aca-OH instead of Fmoc-Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, crude was obtained as described in Example 1 peptide which is purified by chromatography under the conditions described. (5% ca80% 3 in 11 min, retention time 6.85). FAB-MS (M + H) &lt; + &gt; = 1376.2

Example 76

Ac a-Phe-Arg-Phe-D-Al a-Gly-Arg ¹ ·!) - Ile-Asp-Arg-Ile>

Using Fmoc-Aca-OH instead of Fmoc- / b Ala-OH and Fmoc-D-He-OH instead of Fmoc-Met-OH and without Fmoc-Cha-OH, the crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (5% to 80 $ 3 3 in 1 min, retention time 7.10 min).

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

-87Example 77

- Ac a-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-D-Asp-Arg-He ~~~~~~~~~~~~

Using Fmoc-B-Asp (tBu) instead of Fmoc-Asp (tBu) -O OE, Fmoc-Aca-OH instead of Fmoc-Ala Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without Fmoc-Oha- The OH was prepared as described in Example 1, crude peptide, which was purified by chromatography under the conditions described (5% a _and 80% B in 11 mins, retention time 6.60 min).

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

Example 78

Ac α-Phe-D-Arg-Phe-D-Al α-Gly-Arg-Ile-Asp-Arg-He-t Using α-Ph-D-Arg (Mtr) -OH and Fmoc-Aca- OH instead of Fmoc-Ala Ala-OH and Fmoc-Ile-OH instead of Fmoc-Met-OH and without. Fmoc-Oha-OH was prepared as described in Example 1 to give a crude peptide which was purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 6.65 min).

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

Example 79

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

Using Fmoc-D-Phe-OH and Fmoc-Aca-OH instead of Fmoc.-.alpha.-Ala-OH and Fmoc-He-OH in place of Fmoc-Met-OH and without Fmoc-Oha-OH, crude was prepared as described in Example 1. peptide which is purified using chromatography under the conditions described (5¾ to 80% B in 11 min, retention time 6.55 min).

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

Example 80. ..... r H.

-Phe-Arg-? -E-D-Ala-Gly-Arg-ile-Asp-Arg-He2a using Pmoc-ile-OH instead of Fmoc-et et-OH and without Fmoc-Cha-OH and Fmoc-Aca-OH with as described in Example 1, prepared a crude peptide which was purified by chromatography under the conditions described (555 to 80% B in 11 min, retention time 6.55 min).

FAB-MS (M + H) &lt; + &gt; = 1232.5

Example 81 µA-α-Phe-Arg-Phe-D-A1-Gly-Arg-Ile: Asp-D-Arg-He-I _; , _1

2a using Fmoc-D-Arg (Mtr) -OH and Fmoc-He-OH instead of Pmoc-Met-OH and without Fmoc-Cha-OH a crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (5). % to 80% in 11 min, retention time 6.15 min).

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

-89Example 82

- β Ala-Phe-D-Arg-Phe-D-ALα-Gly-Arg-Ile-Agp-D-Arg-Ile-,

2a using Fmoc-D-Arg (Mtr) -0H and Fmoc-Ile-OH instead of Fmoc-Mgt-OH and without Fmoc-Cha-OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5). % ηβ '80% 3 in 11 min, retention time 6.05 min).

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

Example 83

- Arg-Phe-D-Al and -Gly-Arg-Ile-Agp-Arg-Ile η

2a using Fmoc-Ile-OH in place of Fmoc-Met-Ori and without Fmoc-Cha-OH and Fmoc-, 6 Ala-OH, following the procedure described in Example 1, the crude peptide was purified by chromatography under the conditions described (5% to 80%) B over 11 min, retention time 5.45 min).

FAB-MS (M + H) &lt; + &gt; = 1085.5

Example 84

- phy-Al-Phe-D-Arg-Phe-D-Al-Gly-Arg-Ile-Agp-Arg-He2a 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, a crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described.

-90 (5% to 80% B in 11 min, retention time 6.40 min). FAB-MS (M + H) &lt; + &gt; = 1303.7

Example 85

- Al a-Phe-Ag-Cha- Az t-Gly-Arg-Tle - Asp-Arg-Ile-i

2a using Fmoc-Azt-OH instead of Fmoc-D-Ala-OH and Fmoc-Tle-OH instead of Fmoc-Met-OH was prepared as described in Example 1, crude peptide, which was purified by chromatography under the conditions described (5% to 80%) Bza 10 min, retention time 7.20 min).

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

Example 86

Ala-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Tle2 and using Fmoc-Ile-OH instead of Fmoc-Met-OH, a crude peptide was prepared as described in Example 1, which was purified by chromatography described conditions (5% ¹¹⁸ 80% B in 10 min, retention time 6.35 min).

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

Example 87 (- Arg-Chs-D-Ala-Gly-Arg-Tle-Asp-Arg-Tle)

2a using Fmoc-Tle-OH instead of Fmoc-Met-OH and without Fmoc- / ila-OH, the crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described ¢ 5¾ h with 80% 3 in 10 min, retention time 6.10 min).

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

Example 88

-Phe-Arg-Ch and D-Ala-Gly-Arg-Ile-Asp-Arg-Ile Using crude Fmoc-Ile-OH instead of Fmoc-Ile-OH and without Fmoc-Ile-OH following the procedure described in Example 1, the crude peptide was prepared. Purification by chromatography under the conditions described ($ 5 ^to 80% B in 10 min, retention time 8.25 min).

FAB-MS (M + H) &lt; + &gt; - 1238.8

Example 89

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

The peptide synthesis is performed on an ACT200 peptide synthesizer from Advanced ChemTech using an Fmoc strategy using a modified control program. To a 50 ml shaking reactor; 1 g of a 2-methoxybenzyl ester resin from Bachem, Switzerland, was placed on a 0.5 mmol cycle of Fmoc-isoleucine. The following amino acid derivatives were used: Fmoc-Arg (Mtr) -OH, Fmoc-Asp (tBu) -OH, Fmoc-Nle-OH, Fmoc-Lys (BOC) -OH, Fmoc-Gly-OH, Fmoc-DAla-OH , Fmoc-Phe-OH and BOC-Lys (Fmoc) -OH. Couplings are performed using 3 equivalents of Fmoc-amino acid each,

1-hydroxybenzotriazole and dicyclohexylcarbodiimide (coupling time 40 minutes). Following the TNBS assay, coupling incomplete acylation is repeated using the same reagents and excesses. Upon complete acylation, another synthesis cycle is started. The cleavage of the Fmoc-protecting groups is carried out with 2? -Piperidine in DMF (once 3 minutes, once 15 minutes).

Between reactions, the resin was washed with DMF 10 times each. After the construction of the linear sequence BOC-Lys-Arg (Mtr) -PheD-Ala-Gly-Lys (SOC) -Nle-Agp (tBu) -Arg (Mtr) -Ile- on the polymer the resin is thoroughly washed with the carrier? and then treat 5 times with 20 ml of a 1% solution of trifluoroacetic acid in dichloromethane at room temperature for a maximum of 10 minutes (until an intense volume of resin is obtained). The solutions were combined, and concentrated in vacuo. The residue is triturated with ether, the ether is decanted off, the peptide is dried under a stream of nitrogen and taken up in 130 ml of DMF, the pH is adjusted to about 8.5 with triethylamine, the solution is cooled to -20 ° C and 0.2 g is added. (0.75 mmol) diphenylphosphoryl azide. Allow to stand for 48 hours at -20 ° C, 48 hours at 4 ° C. The pH is maintained at 8.5 with triethylamine. It is then removed in vacuo, the residue is triturated twice with ether, the ether is decanted off 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 raw peptide is purified over a 3 µl column. Lynamax C18 (10 x 2.14 cm) using one of the gradients A: water / acetonitrile / trifluoroacetic acid 95/5 / 0.2 and B: dto 20/80 / 0.2 to 5% B to 80% B at 11 minutes, flow rate 20 ml, retention time 5.25 min. After freeze-drying, an amorphous colorless powder is obtained.

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

Example 90

Using Z-Lys (Fmoc) -OH instead of 30C-Ly _S (Fmoc) -OH, the crude peptide was obtained as described in Example 1,

Which was purified by chromatography under the conditions described (5% to 80% B in 11 min. Retention time 6.60 min). FAB-MS (M + H) &lt; + &gt; = 1320.0

Example 91

Z-Lyg-Arg-Ser (Bzl) -D-Ala-Gly-Lys-Nle-Agp-Arg-HeZ using Z-Lys (Fmoc) -OH instead of 90C-Iys (Fmoc) -OH and Fmoc-Ser (Bzl) Instead of Fmoc-Phe-OH, the crude peptide was prepared as described in Example 1 and purified under chromatography as described (5% to 90% B in 11 min, retention time 6.95 min).

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

Example 92

Bz-Lys-Arg-Phe-D-Ala-Gly-Lys-Nle> Asp-Arg-II e Using Bz-Lys (Fmoc.) - OH instead of BOC-Lys (Fmoc) -0H, the procedure described in Example 1 was obtained crude peptide which was purified by chromatography under the conditions described (5% to 80% 3 in 11 min} retention time 6.00 min).

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

Example 93

Z-Lys-Arg-Phe-D-Al and -Gly-Arg-Ile-Agp-Arg-Ile Using Z-Lys (Fmoc) -OH instead of BOC-Lys (Fmoc) -OH and be2 Fmoc-No-OH and Fmoc-lys (BOC) -OH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% 3 in 11 min, retention time 6.65 min).

-94FA 3-MS (M + H) + = 1348.0

Example 94

Η-Ly s-Arg-Cha-D-Ala-Gly-Arg-Ile-Agp-Arg-Ile-1

2a using Fmoc-Cha-OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH, the crude peptide was obtained as described in Example 1, which was purified by chromatography described conditions (5% to 80% B in 11 min, retention time 6.00 min).

FAB-MS (M + H) &lt; + &gt; = 1219.7.

Example 95

Z-Lys-Arg-Cha-D-Al and -Gly-Arg-Ha-Agp-Arg-IIa using Z-Lys (Fmoc) -OH instead of BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH instead Fmoc-Phe-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH were prepared as described in Example 1, crude peptide, which was purified by chromatography under the conditions described (5% to 80%). B over 11 min, retention time 6.35 min).

FAB-MS (B + 1 + H) + = 1353.7

Example 96

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

Using Menoc-Lys (Fmoc) -OH instead of 3OC-Lys (Fmoc) -OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OK, the crude peptide was prepared as described in Example 1. which is purified by chromatography under the conditions described (5 / ¾ to 80 $ Bzall min, retention time 8.20 min). FAB (M + H) + = 1395.8 '

Example 97

Λ

Name-Lys-Arg-Cha-B-Al and -Gly-Arg-Ile-Agp-Apg-IleUsing Menoc-Lys (Fmoc) -0H instead of BOC-Lys (Fmoo) -OH, Fmoc-Cha-OH instead of Fmoc -Phe-OH and Fmoc-Ile-OH instead of Faoc-Nla-OH and without Fmoc-Lys (BOC) -OH, a crude peptide was prepared according to Example 1 and purified by chromatography under the conditions described ($ 20 to $ 80 B). 11 min, retention time 7.00 min).

FAB-MS (M + H) &lt; + &gt; = 1402.0

Priklaď 98

H-Iys-Lyg-Cha-D-Al and -Gly-Arg-Ile-Asp-Arg-Ile-

Using Fmoc-Ile-OH instead of Fmoc-Kle-OH and Fmoc-Cha-OH instead of Fmoc-Phe-OH, the crude peptide was obtained as described in Example 1, which was purified by chromatography under the conditions described (5 $ to 80% B at 11 min, retention time 6.40 min).

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

-96Example 99

Z.-Lys-Lys-Cha-L-Ala-Gly-Arg-Ile-Asp-Arg-Ile-

2a using Z-lys (Fmoc) -OH instead of BOC-Lys (Fmoc) -OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH a crude peptide was prepared as described in Example 1, which was purified by chromatography under the conditions described (5). % to 80% B in 11 min, retention time 7.75 min).

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

Example 100

Z-Lys-Phe-Phe-D-Ala-Gly-Arg-Ile-Aep-Arg-Ilei-I

2a using Z-Lys (Fmoc-OH instead of BooLys (Fmoe) -0H and Fmoc-Ile-OH instead of Fmoc-Nle-OH a crude peptide was prepared as described in Example 1, which was purified by chromatography under the conditions described (5% to 80%). % in 11 min, retention time 8.40 min) »

FAB-MS (M + H) &lt; + &gt; = 1339.0

Example 101 (4-NO2) 2-Lys-Arg-Gha-D-Ala-Gly-Arg-Ile-Agp-Arg-ile2a using U-NQgJZ-LysiFmoc-OH instead of BOC-Lys (Fmoc) -OH, Fmoo> Ile-0H instead of Fmoc-Nle-0H and Fmoc-Cha-OH instead of Fmoc-Phe-OH was prepared as described in Example 1, crude peptide, which was purified by chromatography under the conditions described! 5%

-Me 80% B in 11 min, retention time 8.45 min). FAB-MS (M + H) &lt; + &gt; = 1398.9

Example 102

2-Lys-O-Ch-D-Ala-Gly-Arg-Ile-Agp-4rg-Ile

2a use 2-Lys (Fmoc) -OH instead of BOC-Lys (Fmoc) -0H, Fmoc-Cha-OH instead of Fmoc-Phe-OH and Fmoc-Ile-OH instead ofFococ-Nle-OH and more? Fmoc-Orir (BOC) -OH was prepared as described in Example 1 to give a crude peptide which was purified by chromatography as described (5% to 80% B in 11 min, retention time 7.80 min).

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

Example 103 .....

H-Lys-Arg-SerOzl) -D-Ala-Gly-Lys-Nle-Agp-Arg-Ile- »

2a using Fmoc-Ser (3zl) -0H in place of Fmoc-Phe-OH a crude peptide was prepared as described in Example 1 and purified by chromatography under the conditions described (5% not 80% B in 11 min * retention time 5.55 min ).

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

Example 104

3z-Ly s-Arg-Phe-B-Al and -Gly-Lys-Wle-Agp-Arg-Ile?

Using Bz.LysiFmoe) -OH instead of BOC-Lys (Fmoc) -OH, the crude peptide was obtained as described in Example 1 and purified by chromatography under the conditions described (5% to 80% 3 in 11 min, retention time 6.40). ).

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

-98Example 106

Bz-Lys-Arg-Ser (3zl) -L-Al and -Gly-Lys-Nle-Asp-Apg-Ile Using 3z-Lys (Fmoc) -0H instead of 30C-Lys (Fmoo) -H and Fmoc-Ser (Bzl) -0H instead of Fmoc-Phe-QH gave the crude peptide as described in Example 1, which was purified by chromatography under the conditions described (5% to 80% in 11 min, retention time 6.35 min).

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

Example 107

Tos-Lys-Arg-Phe-L-Ala-Gly-Arg-4-le-α-Arg-11e. I I.—. ι - .1 I ...... ---- - - - .11

Using Tos-Iys (Fmoc) -OH instead of BOC-Lys (Fmoc) -0H and Fmoc-Ile-OH instead of Fmoc-Nle-OH, a crude peptide was obtained as described in Example 1, which was purified by chromatography by chromatography as described above. conditions (5% to .80% B in 11 min, retention time 6.90 min).

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

Example 108

H-Lys-Arg-Phe-Clg-Arg-Ile-Asp-Arg-Ile Using Fmoc-Glg-OH instead of Fmoc-Gly-OH and instead of Fmoc-D-Ala-OH and Fmoc-Ile-OH instead of Fmoc-Nle The crude peptide was purified according to the procedure of Example 1 and purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 4.85 min).

FAB-MS (M + H) + = 1253, ⁸

-99Example 109

Z-Lys-Arg-Phe-Olg-Arg-Ile-Asp-Arfe-Ile Using Z-Lys (Fmoc) -OH instead of BOC-Lys (Fmoc) -QH, Fmoc-Clg-OH instead of Fmoc-Gly-OH and Fmoc-D-ALa-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH gave the crude peptide according to the procedure described in Example 1, which was purified by chromatography under the conditions described (5% na 80 #

B over 11 min, retention time 6.85 min).

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

Example 110

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

Using Z-Lys (Fmoc) -OH instead of BOC-Lys (Fmoc) -QR,

- - Fmoc-Cha-OH 'instead of-Fmoe-Phe-OH and Fmoe-He-OH instead of Fmoc-Nle-OH and Fmoc-Glg-OH instead of Fmoc-Gly-OH and Fmoc-D-Ala-OH and without Fmoc-Lys (BOC) -OH was prepared according to the procedure described in Example 1 and was purified by chromatography under the conditions described (5% to 80% B in 11 min, retention time 8.70 min).

FAB-MS (M + H) &lt; + &gt; = 1394.0

Example 111

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

Using Z-Lys (Fmoc) -0H instead of BOC-Lys (Fmoc) -OH, Fmoc-Cha-OH instead of Fmoc-Phe-OH, Fmoc-Clg-OH instead of Fmoc-Gly-OH

-100a Fmoc-L-Ala-OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without. Fmoc-Lys (BOC) -OH gave the crude peptide according to the procedure described in Example 1, which was purified by chromatography under the conditions described (5% to 80% B 'over 10 min, retention time 9.80 min).

FAB-MS (M + H) &lt; + &gt; = 1393.9

Example 112

H-Dap-Apg-Cha-D-Al α-Gl, γ-Arg-He-Asp-A-g-Ile Using BOC-Dap (Fmoc) -OH instead of BOC-Lys (Fmoc) -OH and Fmoc-Ile-OH instead of Fmoc-Nle-OH and without Fmoc-Lys (BOC) -OH, a crude peptide was prepared according to the procedure described in Example 1 and purified by chromatography under the conditions described (5% to 80% in 10 min, retention time & FAB-MS: (M + H) &lt; + &gt; = 1177.5

Example 113

Z-Dap-Arg-Cha-D-Al and -Gly-Apg-He-Asp-Arg-Ile

Using Z-Dap (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) The crude peptide was prepared according to the procedure described in Example 1 and purified by chromatography using the conditions described (5% to 80% B in 10 min, retention time 8.10 min).

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

(4-NO2) Z-Lys-Arg-Gha-D-Ala-Gly-Arg-Met-Asp-Arg-Ile Analogously Prepared by chromatography under the conditions described (10% to 90% 3 in 10 min, retention time 7.4 min). FA3-MS (M + H) + = 1417.0 (4-NG2) 2-Lys-Grn-Ch-D-Ala-Gly-Apg-Ile-Agp-Apg-II

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

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

Example 114

2-Pyridylacetyl-Lys-Arg-Cha-D-Ala-Gly-Arg-He-Asp-Arg-ηβη

Peptide synthesis was performed on Advanced ChemTech ACT200 peptide synthesizers using an Fmoc strategy using a modified control program. A 50 ml shake reactor was charged with 1 g of 2-methoxybenzyl ester resin from Bachem, Switzerland, which was fed into a 0.5 mmol cycle of Fmoc-isoleucine. The following amino acid derivatives are used: Fmoc-AArg (Mtr) -OH, Fmoc-Asp (t u) -OH, Fmoc-He-OH, Fmoc-Gly-OH, Fmoc-D-Ala-OH, Fmoc- Cha-OH and 2-pyridylacetylLys (Fmoc) -OH. Coupling is carried out using 3 equivalents each of Fmoc-amino acid, 1-hydroxybenzotriazole and dicyclohexylcarbodiimide (coupling time 40 minutes). After the TNBS tests are performed, incomplete acylation of the coupling is reversed? using the same reagents and excess. Upon complete acylation, the next synthesis cycle is started. The cleavage of the Fmoc-protecting groups is carried out in each case with 20% piperidine in DMF (once every 3 minutes, once every 15 minutes).

Between reactions, the resin was washed with 10 times DMF each time.

After construction of the linear sequence of 2-pyridylacetyl-Lys-Arg (Mtr) Cha-D-Al and -Gly-Arg (Mtr) -Ile-Asp (tBu) -Ar (Mtr) -Ile- on the polymeric support, the resin was washed thoroughly with dichloromethane and then treated 5 times with 20 ml of a 1% solution of trifluoroacetic acid in dichloromethane for a maximum of 10 minutes at room temperature (until intense IIIa of resin color). The solutions were purified and evaporated in vacuo. The residue is triturated with ether, the ether is decanted off, the peptide is dried under a stream of nitrogen and taken up. into 130 mL of DMF, the pH is not adjusted to about 8.5 with triethylamiaent, the solution is cooled to -20 ° C and 0.2 g (0.75 mmol) of diphenylphosphorylazidix is added. Allow to stand for 48 hours at -20 ^TT C 48 hours at 4 ° C. The pH is maintained at 8.5 with triethylamine. 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 production. The side chain protecting groups are cleaved for 24 hours at room temperature with trifluoroacetic acid / anisole (90/10). The solution is concentrated in vacuo, the residue is digested with ether and dried. The crude peptide was purified through a 3 µm column of Dynamax C18 (10 x 2.14 cm) using one of the gradients A: water / acetonitrile / trifluoroacetic acid 95/5 / 0.2 and B: dtto 20/80/0 , 2 of 10% Hna 90% B in 11 minutes, flow 10 ml / min _r retention time 8.2 minutes. After freeze-drying, an amorphous colorless powder is obtained.

FAM-MS (M + H) &lt; + &gt; = 1338.6

-103Files 115 to 124

X-Lys-Arg-Cha-D-Al and -Gly-Arg-Ile-Agp-Arg-Use of X-Lys (Fmoc) -OH instead of 2-pyridylacetyl-Lys (Fmoc) -OH was followed according to the procedure described in Example 1 prepared crude peptide, which was purified by chromatography under the conditions described (10% to 90% B 'in 11 min, retention time see table below).

Example

C.

'FAB-MS (M + H) retention time (min)

8.2

9, .5.

8.3

8.7

- ~ 1338.6

9 3.7

1403.6

1325.8

1382.8

1385.8

-104Example ·

δ. X retention fab-ms (m + h) time (min)

120 ^Br 0 7.8 1415.7 (1,417.7) 1 Br 121 oC 0 7.5 1398.8 122 ^cl -O ^0x T 0 8.0 1388 123 03 / • <-y 0 hKoH Λ 8.1 1404 J. '. 124 7.5 1422

(1) i Cleaning deviation according to example 1: 10% B to 90% B in 10 minutes, flow rate 10 ml / min

-105Gel (for transdermal administration, particularly associated with iontophoresis)% of the active substance of the formula I in citrate buffer pH 4.1

0.25% agarose

Composition of citrate buffer pH 4.1

10.5 g citric acid monohydrate /

100.0 ml of 1M sodium hydroxide solution I to 500.0 ml of distilled water J

100.0 ml hydrochloric acid (0.1 mol / l) to 250.0 ml solution I f solution II

The above solution was heated to about 60 ° C with stirring and allowed to cool to room temperature to dissolve all agarose particles.

Solution for injection

10.5 ff NaH 2 PO 4 H 2 O

95.5 g Ns ₂ HP0..12H ₂ O>

22,0 g. NaCl to 5000 ml distilled water is pH 7.4 buffer

This buffer solution is autoclaved at 121 ° C and 30 psi for 30 minutes.

-106

To this solution is added 1.5 g of an active substance of the formula I and the resulting solution is sterile filtered.

For example, a compound of formula (4-NO2) Z-Lys-Arg-Cha-D-Al and -Gly-Arg-Ile-Asp-4g-Ilene or others of the above compounds may be used in the formulation examples.

Claims (19)

PATENTO.V.É. Claims 1 _Λ En is Gly, Asp, or Asn, or Dn and En together represent a 10-amino acid residue of the formula -NH- or a peptide template, preferably Btu, Clg, The or Tpc or their D-forms, especially D-Btu, Gn and Kn independently represent Ile, D-Ile, Met, D-Mefc, Nle, D-Nle, Leu, D-Leu, Val or D-Val, preferably He, Met, Nle or Leu, Hn means HOOC- (0 ') _U4 -CH (NE-) -CO-, its D-foray, Gly, Ala, D-Ala, Asn. D &apos; Asn, Fhe or D-Phe, preferably Asp, Glu or Gly. 1. The cyclopeptides of formula (I) and ANP agonist activity + rAn-Bn-Cn-Dn-En-Fn-Gn-Hn-In-Kn-t (I) wherein the sequence of members Bn to Kn represents the sequence of amino acid residues of hANP Arg (27) -Phe (8) -Gly (9) -Gly (10) -Arg (11) Me + (1) "2. ---- Cyclopeptides of claim 1, wherein the spacer ........ the moiety in the moiety downstream of member Bn contains an aromatic or cycloaliphatic residue. (2) -Asp (13) -Arg (14) -Ile (15) - or its spatially structural and functional equivalents; and An is a spacer group that connects Bn to Kn, and the spatial structure of these molecules is thereby affected by the binding of cyclopeptides to ANP receptors, and pharmaceutically acceptable salts thereof. Cyclopeptides according to claim 1 or 2, wherein the members of Bn, Cn, En, Fn. Gn, Hn In and Kn are in L-form. 4-nitrobenzyloxycarbonyl or 2- or 4-trifluoromethylbenzyloxycarbonyl, Y represents a C1-C14-alkyl radical or a (C1-C14-alkyl) -phenyl radical, preferably benzyl or phenylethyl, -115X ¹ represents phenyl or mono- or di-substituted phenyl, 2-pyridyl, 2-pyrazinyl, 3-benzo / b / thienyl or 2-naphthyl. A cyclopeptide according to any one of claims 1 to 3, wherein Bn is an amino acid residue having one or two side chains, wherein the side chain (s) or one of the two side chains comprises (s) one, two, three or four basic groups, -108Cn is a β-amino acid residue with one or two optionally -O-, -S = or -C (O) O- containing alkyl side chains, wherein the side chain (s) bear (s) or one of them bears the residue or two radicals wherein each radical is cycloalkyl of 3 to 10 carbon atoms, phenyl, naphthyl, substituted-for example hydroxy, phenyl (C ₁ _ ^) alkyloxy, (C _ ^) alkoxy, N0 ₂₎ phenyl or 5-or 6- a membered aromatic heterocycle wherein 2 members represent K or one member H and one is O or S, or one member is K, S or O and are G, preferably thienyl, furyl, pyrrolyl, imidazoles, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoquinolyl, quinolyl, chromanyl, thiazolyl, oxazolyl, morpholinyl, Dn and En each independently of one another is Gly or an ok-amino acid residue that mimics the spatial structure of the native amino acid Gly, or Dn and En together represent the β-amino acid residue -NK zbytekCHg ^ ^CO or the peptide template, Fn is an amino acid residue with one or two side chains, wherein the side chain (s) or one of the two side chains comprises (s) one, two, three or four basic groups, Gn je? 4-amino acid residue with one or two lipophilic side chains, Hn is a--amino acid residue that does not contain any functional group in the side chain (s) or: -COOH or -CONH 2 contains as a functional group, ± n is _ε- amino acid residue with one or two -109 side chains, wherein the side chain (s) or one of the side chains comprises one, two, three or four basic groups, Kn is an N-amino acid residue with one or two lipophilic side chains, The cyclopeptide of claim 4, wherein Bn, Fn and In independently represent o (a side chain amino acid residue, wherein the side chain comprises one or two basic groups, Gn is a sidechain amino acid residue, Dn {and En are independently of one another as defined in claim 4 or. of Dn and En Spůle forms -amino acid residue -NH- (CH _{2) 2} .5 ^"co ~ · nebn tepilát peptide, GnT does not depend on the ammonium acid --------------- a new residue with a lipophilic side chain, wherein the side chain is (O - (-)) alkyl, which may also contain one or two -S- or -O- in the chain, i Hn is a Gly or -amino acid residue whose side chain is (C 1 -C 6) alkyl, phenyl- (C 1 -C 6) -alkyl, 1 N-CO-C 1-6 or H ₂ O 6 - (CH ₂ ) _1-4 - _t ' The cyclopeptide of claim 5, wherein Bn, Fn and In independently represent Arg, D-Arg, lys, D-Lys, Orn, D-Or, homo-Arg, D-homo-Arg-Lap, D-Dep or 4-amino-Phe, preferably Arg, D-Arg., Lys, D-Lys or Orn, -110On means Phe, D-Phe, α-NO 2 -Phe, Cha, D-Cha, Ser (Bzl), D-Ser (3zl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr (Bzl) ), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-AGP (Bzl), His, D-Hi _s ^G lu (Bzl), or D-Glu (Bzl), preferably Phe; Cha, Tyr, Nal, Tyr (Bzl), or _(4-NO2) -Phe, Dn and En independently represent 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, A cyclopeptide according to any one of claims 1 to 6, wherein An je a) -A ^ A ^ A ^ -, wherein, _ A ^ is Gly or an o (, - amino acid residue whose side chain (s) do not resist any functional groups, 8th ⁷ cyclopeptide according to claim 7, wherein Ar represents a), wherein A 1 is a--amino acid residue having one (C 1-6) alkyl side chain, A 1 is an amino acid residue of formula II wherein n is an integer from 1 to 6, A 1 is a single side chain amino acid residue, or A 1 = A 1 = A 1 where A 1 is an A 1 amino acid residue of formula II wherein n is an integer from 1 to 6, Aiji is (A-amino acid residue with one side chain, c) an amino acid residue of formula III wherein m is 1, 2, 3 or 4 and R is -NHX, -NHY, -NHIHJ-CIJJ-CHg-X ¹ , -ff (H) -C (O) -CH ₂ -O-X, -N (H) -C (O) -X ¹ , -N (H) -C (O) -CH = ^CH-X-I or -FTÍHJ CCOÍ-CH -X ^first The cyclopeptide of claim 8, wherein An is (a) the group where A 1 is Ala, Gly. Phe, IIa, Ile, Leu or Nle or their D-form, preferably Gly, Ala or D-Ala, A, is <(u) - an amino acid residue of formula II wherein n is 2,3 or 5, -114A ^ means Phe-, D-Phe, 4-NO ₂ -Phe, Cha, D-Cha, Ber (Bzl), D-Ser (3zl), Tyr, D-Tyr, TyrOzl), D-Tyr (3zl) ), Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Agp (Bzl), His or D-His, preferably Phe, Tyr, Cha, Nal or (4NO ₂ ) Phe ₂ , or b) the group -A 1 -A 1 -, wherein the radical (O-amino acid of the formula II) wherein n is 2, 3 or 5, A ^ is Phe, D-Phe, 4-NO2, Phe, Cha, D-Cha, Ser (Szl), D-Ser (Bzl), Tyr, D-Tyr, Tyr (Bzl), D-Tyr (3zl) , Nal, D-Nal, Thi, D-Thi, Asp (Bzl), D-Asp (3zl) _HIS-;, D-His ol (Bzl), or D-Glu (Bzl), preferably Phe, Tyr, Cha , N-α1 or β-NOg β-Phe, or c) an amino acid residue of formula III wherein m is 1, 2, 3 or 4 and H is as defined in claim 8, wherein X represents hydrogen, unsubstituted or chloro, methoxy or (C1-C3) alkyl-substituted benzoyl, cyclohexyloxy- or mentyhloxycarbonyl, unsubstituted or methoxy, nitro, trifluoromethyl or cyano-substituted benzyloxycarbonyl, preferably benzyloxycarbonyl 1,4-methoxybenzylo. yl, 2 or 4-trifluoromethylbenzylcarbonyl or 4-nitrobenzyloxycarbonyl, in particular benzyloxycarbonyl, The cyclopeptide of claims 1 to 9, wherein An is -A 1 -A 1 -A 1 -, where Gly, A 1 is Aia, JUa, Apen, Abut, Gly or a covalent bond, and A 1 is Phe, Phe (4-NO ₂ ), Tyr or Tyr (Bzl), or An is a group -A 1 -A 1 - wherein is Ala, Aca, The, Aund, Btu or D-Bttr and is a covalent bond, Phe, D-Phe, Phe (4-NO ₂ ), Tyr, Tyr (Bzl) or Cha, or A 1 is an amino acid residue of formula III. > -NH-CCH3-CR1-CO-, wherein m. Is 1 or 4 and S is -NHX, wherein X is H, Z, Bz, Menoc, (4-NO-) Z 2 2 or Tos or An is X -lys-, wherein X is one of the following groups 116 O -117Bn is Arg, D-Arg, lys, Orn, or Ctr, Cn is Cha, Phe, Ser (Bzl), Tyr, Tyr (Bzl), or Tyr (Me), Dn is D-Ala, Pro or D-Pro, En is Gly, or Dn and En together form L-Clg, D-Clg or D-Btu, Fn is Arg or Lys, θη is Ile :, D-Ilee, Nle or Met, Kn is Agp, D-Asp or Gly, In is Arg or D-Arg and Kn is Ile ?. The cyclopeptide of claim 10, wherein An is -Gly-fcAla-Phe-, -Gly-Λ Al and-Tyr (Bzl) -, ^7th Ala-Phe, (z1-NC2N2Z-Lys Bn is Arg, Lys, Cr or. Orn, Cn is Cha or Phe, Dn is D-Ala, En is Gly, Fn is Arg, Gn is Ile or Met, Asp n is ^8, In is Arg and Kn is Ile. -11812. Cyclopeptide according to claim 1 CA-Phe-Arg-Phe-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly BAla-Tyr (Bzl) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-Gly-BAla-Phe-Arg-Cha-D-Ala-Gly-Arg-IIe-Asp- Arg-Ile BAla-Phe Lys-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile -Bala-Phe (4-NO2) -Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile f-fla-Phe-Ctr-Cha-D-Ala-Gly-Arg-Ile-Asp -Arg-Ile _(4-NO2) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile AND X-Lys-Arg-Cha-D-Ala-Gly-Arg-Arg-Ile-Asp-Arg-Ile- (4-NO-) Z-Lys-Arg-Cha-D-Ala-Gly-Arg-Met-Asp- Arg-Ile-, ² I_____J (4-NO ² ) Z-Lys-Orn-Cha-D-Ala-Gly-Arg-Ile-Asp-Arg-Ile-L- - pharmaceutically acceptable salts thereof * -119 » J -11 represents a covalent bond or a cn-amino acid residue of the formula: IX -NH- (CH ₉ ) -CO- (II)? Ft where n is an integer from 1 to 11, An represents an amino acid residue with one or two optionally -O-, -5- or -O (O) O- containing alkyl side chains, wherein the side chain (s) or one of the two side chains carries one or two residues, each each of said radicals is C 3 -C 10 cycloalkyl, phenyl, naphthyl, substituted (e.g., hydroxy, phenyl (C 1-4) alkyloxy, (C 1-4) alkoxy, NO ₂ ) -phenyl or 5- or 6-cycloalkyl; -the articulated aromatic he ter o cycle where 2 ring members? is K or one member is N and one Q or S, or one member is IR, S or O, and the other members are C 'preferably thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl , isoquinolyl, quinolyl, chromanes, thiazolyl, oxazolyl, morpholinyl, ------- or b) a group -A 1 - A 1 -, wherein A - - - - -. Ί —— J - - - 1 4 - λ, Zeeiameue pepvxuvv.y veiupxa in ueuu Lv-amxnus / y aexxnuvy residue of formula II -NH-ICl-COIt (II) -112 where n is an integer from 1 to 11, denotes a covalent bond or ¢ (-amino acid residue with one or two optionally -O-, -S- or -C (O) O) containing alkyl side chains, wherein the side chain (e) or one of the two side chains does not have one or two radicals, each of which is a cycloalkyl of 3 to 10 carbon atoms, phenyl, nephtyl, substituted (e.g., hydroxy, phenyl (C 1 -C 4) alkyloxy, (C 1 -C 6 alkoxy), NO 2 -phenyl, or a 5- or 6-membered aromatic heterocycle wherein the two ring members are N or one member is K 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, piperazinyl pyrida- in, indolyl, isochinol.yl, quinolyl, chromenyl _r thiazolyl, oxazolyl, morpholinyl, or c) an amino acid residue of formula III -NH-CH3-CH (E) -CO (III) wherein m is an integer from 1 to 11 and R is NHX, OX, SX, NXY, -NH (H) -C (O) -CH ₂ -X ', -N (H) -O (O) -CH ₂ -O-X ¹ , -N (H) -C (O) -X ¹ , -N (H) -C (O) -CH = CH-X ¹ or -N (H) -C (O) -O-CH ₂ -X ¹ , wherein X is hydrogen, unsubstituted or substituted benzoyl, unsubstituted or substituted 2-cyclohexyloxycarbonyl, unsubstituted or substituted benzyloxycarbonyl, 2-, 3- or 4-pyridylmethyloxycarbonyl or tosyl, X represents a C 1 to C 14 -alkyl radical or an aryl- (C 1 to C 14 -alkyl) radical and -113X ¹ is (-) fehyl (β) of 1,2 or 3 substituents selected from halogen, trifluoromethyl or nitro-substituted phenyl, (fy) naphthyl, () ber.zo / b / thienyl, (£ Jpyridyl or (* in (pyrazinyl). A method for producing cyclopeptides according to any one of claims 1 to 12, or salts thereof, characterized in that a linear peptide sequence from the corresponding fragments is exposed by methods known in peptide chemistry and then cyclized and, if desired, converted to the corresponding salt. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12. Use of a compound according to any one of claims 1 to 12 for the manufacture of an antihypertensive agent or a hypotensive agent. 16. Use of the compound according to? One of claims 1 to 12 for the manufacture of a diuretic. Use of a compound according to any one of claims 1 to 12 for the production of a vasodilator. Use of a compound according to any one of claims 1 to 12 for the manufacture of a spasmolytic. Use of a compound according to any one of claims 1 to 12 for the manufacture of a broncholytic.