SK121793A3 - Cyclopeptides - Google Patents

Abstract

The invention relates to novel cyclopeptides of the formula I Cyclo-(A-B-C-D-Arg) I in which A and B in each case independently of one another denote Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val, C denotes Asp or Asp(O-C1-4-alkyl) and D denotes Gly or Ala, at least two of the amino acid radicals indicated being present in the D-form, and their salts. These compounds act as integrin inhibitors and can be used in particular for the prophylaxis and treatment of circulation disorders and in tumour therapy.

Description

Technical field

The invention relates to novel cyclopeptides of the general formula I cyclo- (A-D-C-D-Arg) (1), wherein:

Q o Q is independently Ala, Asn, Asp, Arg,

Cys, Gin, Glu, Gly, Yis, Tie, Leu, L.ys, Flight, Phe,

Pro, Ser, Thr, Trp, Tyr, or Val,

C is Asp or Asp (O-C 1-6 -alkyl); and

C is Gly or Ala, wherein at least two of said amino acid residues are in the D-form as well as their salts.

BACKGROUND OF THE INVENTION

Probable compounds are known from Phrmazic 40 (8),

532-535 (1985).

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds with valuable properties, in particular those which can be used for the manufacture of medicaments.

It has been found that the compounds of the formula I and their salts have very valuable properties. In particular, these compounds act as inhibitors, suppressing, in particular, the interaction of IK-inteprine receptors with 1.igan2 eight. This effect can be demonstrated, for example, by the method of J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). In addition, the compounds exhibit anti-inflammatory effects. All of these effects can be demonstrated by methods known in the literature.

The compounds can be used as active substances for medicaments in human and veterinary bladder, in particular for the prophylaxis and treatment of circulatory diseases, thrombosis, heart attack, arteriosclerosis, inflammations, apolexia, angina pectoris, malignant tumors, osteological diseases, in particular osteoporosis. , angiogenesis and restenosis after angioplasty.

In the foregoing and following text, the following abbreviations of amino acid esters are used for residues of these amino acids:

Ala

Asp

Asp (OR)

Arg

Cys

gin

Glu

Gly

Uis

Ile

Leu

Lys

Ide t

Phe

Pr ₀

Ser

Thr

Trp alanine asparagine aspartic acid ester / arginine cysteine glutamine glutamic acid glycine histidine

Isoleucine leucine lysine methionine phenylalanine proline serine threonine durptophan

- 3 Tyr tyrosine

Val vslín.

Other abbreviations are also used below, which means

BOC tert-butoxycarbonyl

CBZ benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

MPF dimethylformamide

EDCI N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride

Et ethyl

FMOC 9-Fluorenylmethoxycarbonyl

KOBt 1-hydroxybenzotriazole

Me methyl

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

Obut tert-butyl ester

OMe methyl ester

OEt ethyl ester

POA phenoxyacetyl

TFA trifluoroacetic acid.

If the aforementioned amino acids can have a plurality of enantiomeric forms, all of these forms as well as mixtures thereof (e.g. DL-forms), for example, as part of the compounds of formula I, are included in the foregoing.

The present invention further provides a process for the preparation of a compound of formula (I) above, or a salt thereof, which comprises releasing from its functional derivative by treatment with a solvolyzing or hydrophenolysing agent or a peptide of formula (II).

11-Ζ-ΟΗ / 11 /, in which

Z is A-B-C-D-Arg-,

-B-C-D-Arg-A-,

-C-D-Arg-A-B,

-D-Arg-A-b_c- or -Arg-A-B-C-D-, or a reactive derivative of such a peptide, is treated with a cyclizing agent and / or the basic or acidic compound of formula I is converted by treatment with an acid or base into its salt.

They have residues in the foregoing and in the following

A, B, C, D and Z have the meanings given in formulas I and II unless expressly stated otherwise.

In the above formulas, alk is preferably methyl, ethyl, isopropyl or tert-butyl.

The group A is preferably Val, in particular D-Val. B is preferably Phe, in particular D-Phe. C preferably represents Asp, in particular D-Asp. Preferably D is.

In this respect, the invention relates in particular to compounds of the formula I in which at least one of the abovementioned residues has the abovementioned preferred meanings.

A preferred group of compounds may be represented by the partial formula Ia, which otherwise corresponds to the general formula I, but in which the

- 5 represents D-Val means Phe represents Asp and represents Gly or Ala.

The compounds of the formula I as well as the starting compounds for their preparation are usually prepared by known methods, as described in the literature (for example, in basic works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Ihieme-Verlag, Stuttgart). under reaction conditions known and suitable for the above reactions. It is also possible to use variants which are known per se but not mentioned here.

The starting compounds may also be formed in situ, if desired, so that they do not need to be isolated from the reaction mixtures when used to react to the compounds of formula I.

The compounds of formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular by hydrolysis, or hydrogenolysis.

Preferred solvolysis or hydrogenolysis starting compounds are those which contain corresponding protected amino and / or hydroxy groups in place of one or more amino and / or hydroxy groups, preferably those which bear an amino protecting group in place of the hydrogen atom attached to the nitrogen atom. , for example, those which correspond to the general formula I, but contain, in place of the amino group, a group of the formula NHR * in which R * represents a protecting group, for example BOC or CBZ.

Further preferred are starting compounds which contain a hydroxyl protecting group in place of the hydroxyl group, for example those which correspond to the general formula I, but instead of the hydroxyphenyl group they contain an RO-phenyl group, wherein R is a hydroxyl protecting group.

A plurality of the same or different protected amino and / or hydroxy groups may also be present in the molecule of the starting compound. If the protecting groups present are different from each other, they can in many cases be selectively cleaved.

The term amino-protecting group is generally known and refers to groups that protect / block / amine from a chemical reaction and which are readily cleavable after the desired chemical reaction has been carried out at other sites in the molecule. Typically, such compounds are unsubstituted or substituted acyl groups. , aryl, aralkoxymethyl or saralkyl groups. Since the amino protecting group is cleaved after the desired reaction (or reaction sequence), its type and size is generally not critical, but preferably those containing 1 to 20 carbon atoms, in particular 1 to 8 carbon atoms, are used.

The term acyl group is to be understood in the context of the present method in the broadest sense. The term includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids; in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl or butyryl, aralksnoyl groups such as phenylacetyl, arovyl groups such as benzoyl or toluyl, aryloxyalkanoyl groups such as POA, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl;

2,2,2-trichloroethoxycarbonyl, BOC or 2-iodoethoxycarbonyl, aralkoxycarbonyl groups such as CBZ (carbobenzoxy), 4-methoxybenzyloxycarbonyl or FMOC and arylsulfone groups such as Mtr. Preferred amino protecting groups εΰ BOC and Mtr, further CBZ, benzyl and acetyl.

The term hydroxyslrupin protecting group is also generally known and refers to groups that are useful for protecting a hydroxy group from a chemical reaction but which are readily cleaved after the chemical reaction has taken place elsewhere in the molecule. Typical such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl groups. The nature and size of the hydroxy protecting groups is not critical, since the hydroxy protecting group is cleaved again after the desired reaction or reaction sequence, but those having 1 to 20 carbon atoms, especially 1 to 10 carbon atoms, are preferred. Examples of hydroxy protecting groups include, but are not limited to, benzyl, p-nitrobenzyl, p-toluenesulfonyl, and acetyl, with benzyl and acetyl being particularly preferred. The carboxy groups in aspartic acid and glutamic acid are preferably protected in the form of their tert-butyl ester (e.g. Asp (OBut)).

Functional derivatives of the compounds of formula I used as starting compounds can be prepared by conventional methods for the synthesis of amino acids and peptides, such as those described in the basic works and patent applications, for example by the solid phase method of Merrifield / B. F. Gysin and R. B. Merrifield, J. Am, Chem.

oc. 24, 3102 et seq. / 1972 //.

The release of the compounds of the formula I from their functional derivatives is carried out, depending on the functional group used, for example by the action of strong acids, preferably an acid.

But also by the action of other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid or sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are preferably organic solvents such as carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, as well as Mixtures of the abovementioned solvents are also suitable. Trifluoroacetic acid is preferably used in excess without addition of an additional solvent perchloric acid in the form of a mixture of acetic acid and 70% sulfuric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are suitably from about 0 to about 50 ° C, preferably at a temperature from 15 to 30 ° C (room temperature).

The BOC, OBut and Mtr groups can be advantageously cleaved by treatment with trifluoroacetic acid in dichloromethane or by treatment with 3- to 5-normal hydrochloric acid in dioxane at a temperature of from 15 to 30 ° C. The FMOC group can be cleaved by treatment with an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in dimethylformamide at a temperature of 15 to 30 ° C.

Hydrogonolytically cleavable protecting groups (e.g., CBZ or benzyl) can be removed by treatment with hydrogen in the presence of a catalyst (e.g., a precious metal catalyst such as palladium, preferably on a support such as charcoal). for example, alcohols such as methanol or ethanol

- 9 nol, or smides such as dimethylformamide. The hydrogenolysis is usually carried out at temperatures of about 0 to 100 ° C and a pressure of about 100 kPa to 20 MPa, preferably at a temperature of 20 to 30 ° C and a pressure of 100 kPa to 1 MPa. Hydrogenolysis of the CBZ group performs well, for example, to 5% to 10% palladium on carbon in methanol or by treatment with ammonium formate at a temperature of from 20 to 30 ° C.

Compounds of formula I may be obtained by cyclization of compounds of formula II under conditions for peptide synthesis. This is conveniently carried out by conventional methods known for the synthesis of peptides, such as those described in Rouben-Weyl, cited above, vol. 13/11, p. 1-806 (1974).

The reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodilmide such as DCCI or CDCl 2, hereinafter propane-sulfonic anhydride / por. Ange'Vi Chem. £ 2, 129 (1980)], diphenylphosphoryl azide or 2-ethoxy-1H-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane an amide such as dimethylformamide or diraethylacetamide; ntrile such as acetonitrile or mixtures of these solvents at temperatures from about -10 to 40 ° C, preferably from 0 to 30 ° C. In order to promote intramolecular cyclization of the intramolecular peptide bond, it is expedient to work in a dilute solvent (dilution principle).

Instead of the compounds of formula II, reactive derivatives of these compounds may also be used in the reaction, for example those in which the reactive groups are intermediately blocked with protecting groups. The amino acid derivatives of the general formula II can be used, for example, in the form of their activated esters which are conveniently formed in situ, not by addition of HOBt or N-hydroxysuccinimide.

The starting compounds of formula II are generally novel compounds ¹ to · the 'add ^A ND manufactured by known methods, for example methods described above for peptide synthesis and of elimination of protecting groups.

Usually, in particular, the ROP-pentapeptide of the general formula R * -Z-OR 'is synthesized, for example BOC-Z-OMe or BOC-Z-OEt, which is first saponified to acids of the general formula R * -Z-OH , for example BOC-Z-OTI, and the R * protecting group is cleaved from this compound to give the free peptides of formula II

K-Z-OH (11).

The base of formula I can be converted by treatment with an acid to the corresponding acid addition salt. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, inorganic acids such as sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, or sulfamic acid, and furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monohydric or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, melonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid , malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanes Ifonic acid, ky ethanedisulfonic acid, 2-hydroxyethane * sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid, naphthalenedisulfonic acid, and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula E.

T

On the other hand, the acid of formula (I) is converted by treatment with a base into its physiologically acceptable metal or ammonium salt. Suitable salts are, in particular, the sodium, potassium, magnesium, calcium and calcium salts. ammonium, aria substituted ammonium salts, for example dimethylammonium, diethylammonium or diisopropylammonium salt, monoethanolammonium, diethanolammonium or triethanolammonium salt, cyclohexylammonium salt and the like. cyclohexyl ammonium salt, dibenzylethylenediammonium salt, for example salts with N-methyl-D-plucamine or arginine or lysine.

The novel compounds of the formula I and their physiologically acceptable salts can be used in the manufacture of pharmaceutical compositions if they are brought into contact with at least one carrier or excipient and, if necessary, with at least one other active ingredient in a suitable dosage form. . The compositions thus obtained can be used as medicaments in human and veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for anteral (e.g. oral or rectal), parenteral (e.g. intravenous injection) or topical (e.g. topical, dermal, ophthalmic or nasal) applications or for use in the form of inhalation sprays and . do not react with the new compounds, such as water, aqueous isotonic sodium chloride solutions, lower alcohols, vegetable oils, benzyl alcohol, polyethylene glycols, glycerin triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starches, *

magnesium stearate, talc, cellulose and petrolatum. For oral administration, particular tablets, dragees, capsules, syrups, swelling or drops are used, and are of interest. specially coated tablets or capsules with gastric juice-resistant coatings or coated capsules. For rectal use, lace, solutions for parenteral administration, preferably olive or aqueous solutions, suspensions, emulsions or implants are used. Suitable for topical use are, for example, solutions which are used in the form of eye drops, for example, suspensions, emulsions, ointments or compresses. For use as inhalation sprays, such sprays may be used which contain the active ingredient dissolved or suspended in a propellant gas or a propellant mixture (e.g., carbon dioxide or fluorinated and simultaneously chlorinated hydrocarbons). The active ingredient is expediently used in a raicronized form, and one or more additional physiologically compatible solvents such as ethanol may be added. Inhalable solutions may be administered using conventional inhalers. The novel compounds can also be lyophilized and the resulting lyophilisates used, for example, for the preparation of injectables. The injections may be administered as a bolus or a continuous infusion (e.g. intravenous, intravascular, subcutaneous or intrathecal). Said compositions may be sterilized and / or may contain adjuvants such as preservatives, stabilizers and / or wetting agents, emulsifying agents, salts ηβ affecting osmosis pressure, buffers, coloring agents and / or flavoring agents. The compositions may, if desired, also contain at least one additional active ingredient, for example one or more vitamins

In general, the compounds of the invention can be administered analogously to known peptides commercially available, in particular the compounds described in U.S. Pat. No. 4,472,305, preferably at a dosage of from about 0.05 to 500 mg, in particular from about 0.5 to about 100 mo, per dosage unit. The daily dose is preferably from about 0.01 to about 0.01

2 mg / kg body weight. However, the particular dose for each particular patient will depend on various circumstances, such as the efficacy of the particular compound used, age, body weight, general health, sex, cost, time and duration of administration, elimination rate, drug combination and the severity of the disease. concerns therapy. Parenteral administration is preferred.

DETAILED DESCRIPTION OF THE INVENTION

As used hereinbefore and hereinafter, temperatures are indicated in degrees Celsius as usual. In the examples below, conventional processing is considered to be followed by adding water as necessary, neutralizing with extraction with ether or dichloromethane, phase separation, drying of the organic phase with sodium sulfate, filtration, evaporation and purification by silica gel chromatography and / or crystallization. RD indicates retention time (in minutes) on high performance liquid chromatography on a column packed with LiChrosorb RP select B (250-4.7 µm), eluent: 0.3% trifluoroacetic acid in water, isopropanol gradient from 0 to 80% v / v 50 minutes at a flow rate of 1 ml / min, detection is performed at 215 nm. M denotes the molecular peak in the mass spectrum obtained by the fast atom bombardment technique.

Example 1

A solution of 30 mg of cis- (D-Val-L-Phe-D-Asp (OBut) -Gly-P-Arg (4tr)) / which can be obtained by cyclization of HD-Arg (Mtr) -1 '-Val-L- Phe-D-Asp (Obut-Gly-OH by the method of Example 2) in 840 µl of TFA, 170 µl of dichloromethane and 85 µl of thiophenol was allowed to stand at 20 ° C for 2 hours and then evaporated under reduced pressure at 37 ° C and lyophilized after dilution with water After gel filtration using Sephadex G 10 in a mixture of acetic acid and water in a ratio of

1: 1 followed by purification by high performance liquid chromatography on a column packed with LiChrosorb RF 8 with an isopropanol gradient in 0.3% TFA in water yields cyclo- (D-Val-L-Phe-D-Asp-gly-D- Arg), RD 17.9, H ⁺ 375.

In an analogous manner there are obtained:

from cyclo- (D-Vcl-D-Phe-D-Asp (OBut) -Gly-D-ArgQitr)) cyclo- (.D-Val-D-Phe-D-Asp-Gly-D-Arg), RD 18.5, M ⁺ 575, from cvklo- (D-Val-D-Phe-L-Asp (OBut) -Gly-D-Arg (Mtr)) cvklo- (L-Val-D-Phe-L-Asp Gly-D-Arg), R D 19.3, ^M-575, from c.yklo- (D-Val "L-Phe-Asp-R (pBut} -L-Ala-R-ArgO ^'d' th I-cyclo- (D-Val-D-Phe-D-Asp-L-Ala-R-Arg '), RD 20.3, M ⁺ 589, from cyclo- (D-Val-D-Phe) -D-Asp (OMe) -Gly-L-Arg (Mtr)) cyclo- (D-Val-D-Phe-D-Asp (OMe) -Gly-L-Arg), RD 21.4,584 from cyclo - (D-Val-D-Phe-L-Asp (OBut) -Gly-L-Arg (Mtr)) cyclo- (D-Val-D-Phe-L-Asp-Gly-Lr-Arg '), from cyclo- (L-Val-D-Phe-D-Asp (OBut) -Gly-L-Arg (lt)) cyclo- (L-Val-D-Phe-D-Asp-Gly-L-Arg), from cyclo- (D-Val-L-Phe-D-Asp (Obut-4-Gly-L-Arg (1'tr)) cyclo-D-Val-L-Phe-D-Asp-Gly-L- Arg}, from cyclo- (L-Val-D-Phe-L-Asp (OBut) -Gly-D-Arg (Mtr)) cyclo- (L-Val-D-Phe-L-Asp-C-ly- D-Arg '), from cyclo- (D-Val-L-Pbe-L-Asp (OBut) -Glv-D-Arg (Mtr)) cyclo- (D-Vel-L-Phe-L-Asp-Gly) -D-Arg), from cyclo- (_-L-Val-L-Phe-D-Asp-OB (OBut) -Gly-D-Arg (Mtr)) cyclo- (L-Val-L-Phe-D-Asp-Gly) D-Arg}

- 15 from cyclo- (L-Val-D-Phe-L-Asp-D-Ala) -D-Ala-L-Arg (Mtr)) cyclo-L-Val-D-Phe-L-Asp-D-Ala -L-Arg), from cyclo- (D-Val-L-Phe-L-Asp (OBut) -D-Ala-L-Arg (Mtr)) cyclo- (D-Val-L-Phe-L-Asp) -D-Ala-4-Arg),. from cyclo-IL-Val-L-Phe-D-Asp (OBut) -D-Ala-L-ArgQ-nitrile) cyclo-L-Val-L-Phe-D-Asp-D-Ala-L- Arg) az cyclo-CL-Val-L-Phe-L-Asp-But-D-Ala-D-ArgO-tr) cyclo- (L-Val-L-Phe-L-Asp-D-Ala- D-Arg}.

Example 2

Solution 80 mg HL-Arg-D-Val-D-Phe-D-AspiOMe-Gly-OKa / which can be obtained by cleavage of the FMOC group from FMOC-L-Arg-D-Val-D-Asp (OMe} -Gly -O-Wang, where O-Vang is a 4-oxymethylphenoxymethyl polystyrene residue used in the Merrfteld synthesis, crosslinked with 1% p-divinylbenzene, treated with morpholine and cleaved the pentapeptide from the polymer by treatment with 1: 1 TFA / dichloromethane DMF (8 ml) was diluted with dichloromethane (72 ml) and treated with 34 mg of finely powdered sodium bicarbonate, dried after solid carbon dioxide (9) acetone mixtures, 34 µl of diphenylphosphoryl azide was added and allowed to stand at 20 ° C for 16 hours. dichloromethane at 37 [deg.] C. The remaining solution was subjected to gel filtration (on a Seph.adex G10 column with an isopropanol / water ratio of 8: 2) and then subjected to a column chromatography on a polymer (Mitsubishi MCI CHP-20P) using isopropanol. gradient in water. There was thus obtained cyclo- (D-Val-D-Phe-D-Asp (OMe) -Gly-L-Arg), RD 21.4, M ⁺ 589.

The above examples relate to pharmaceutical compositions.

Example Λ: Vials

A solution of 100 g of the cyclopeptide of the formula I with 5 g of sodium hydrogen phosphate in 3 liters of double-distilled water with? Adjust to pH 6.5 with 2 N hydrochloric acid, filter sterile, fill into vials, lyophilize under sterile conditions and seal sterile. Each vial contains 5 mg of active ingredient.

Example B: Lace

A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

A solution is prepared from 1 g of an active compound of the formula I, 9.3B g of sodium dihydrogen phosphate dihydrate, 28.48 g of disodium hydrogen phosphate dodecahydrate and 0.1 g of benzalkonium chloride in 940 ml of twice, distilled water. the pp value is adjusted to 6.8, the solution is made up to 1 liter and sterilized. exposure to radiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of an active compound of the formula I are mixed

- 17 with 99.5 g of petroleum jelly under aseptic conditions.

Example E: Tablets

A mixture of 100 g of cyclopeptide of formula I, kg of lactose, 600 g of microcrystalline cellulose, 600 g of corn starch, 100 g of polyvinylpyrrolidine, 80 g of talc and 10 g of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. .

Example F: T. frozen

The tablets are compressed as in Example E and then coated in a conventional manner with a coating of sucrose, corn starch, talc, tragacanth and dye.

Example G: Capsules

In a conventional manner, hard gelatin capsules are filled with the active ingredient of the formula I, in such a way that each capsule contains 5 mg of the active ingredient.

Example H: Inhalation spray g of active compound of the formula I are dissolved in 10 l of isotonic sodium chloride ch ¹ and the solution is filled into commercially available spray containers of provisions pumping mechanism. The solution may be sprayed into the mouth or nose. The spray volume (about 0.1 ml) corresponds to a dose of about 0.14 mg · active ingredient.

Claims (11)

PATENT CLAIMS Cyclopeptides of the general formula I cyclo- (A-B-C-D-Arg) (1), wherein: A and B are each independently Ala, Asn, Asp, Arg, Cys, Gin, Glu, Gly, His, Il, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val, C is Asp or Asp (O-C 1-4 alkyl); D is Gly or Ala, wherein at least two of said amino acid residues are. in D form, as well as their salts * 2. cyclo- (p-Val-L-Phe-D-Asp-Gly-D-Arg). 3. cyclo- (D-Val-D-Phe-D-Asp-Gly-L-Arg). 4. cyclo- (D-Val-D-Phe-L-Asp-Gly-D-Arg). 5. cyclo-D-Val-D-Phe-D-Asp-L-Ala-D-Arg). 6. cyclo- (D-Val-P-Phe-D-Asp (OMe) -Gly-L-Arg). 7. Preparation of the compound of formula I according to claim 1 or a salt thereof, wherein _t characterized by liberating them from their functional derivatives by treatment with a solvolysing or hydrogenolysing agent. or a peptide of formula II - 19 ΙΙ-Ζ-ΟΗ / η /, in which Z is A-B-C-D-Arg-, -BCD-Arg-A-, ^{-CD-of-Arg-Β-} Λ, -D-Arg-A-B-C- or -Arg-A-B-C-D-, or a reactive derivative of such a peptide, is treated with a cleaving agent and / or the basic or acidic compound of formula I is converted by treatment with acid or base to its salt. A process for the manufacture of pharmaceutical compositions, characterized in that in a suitable dosage form, the compounds of the formula I according to claim 1 and / or a physiologically acceptable salt thereof are brought into contact with at least one solid liquid or semi-solid carrier or excipient. Pharmaceutical composition, characterized in that it comprises at least one compound of the formula I according to claim 1 and / or a physiologically acceptable salt thereof. Use of the compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament. Use of the compounds of the general formula T according to claim 1 and / or their physiologically acceptable salts for controlling diseases.