SK280597B6 - Cyclopeptides, method of their preparation, pharmaceutical compositions them containing and their use - Google Patents

Abstract

The invention relates to novel cyclopeptides of the formula (I) Cyclo-(A-B-C-D-Arg), 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, osteolytic disorders, in particular osteoporosis, for angiogenesis and restenosis after angioplasty.

Description

The invention relates to cyclopeptides, processes for their preparation, pharmaceutical compositions containing them and their use as integrin inhibitors for the prophylaxis and treatment of circulatory diseases and in the treatment of malignant tumors and ostcolytic diseases, in particular osteoporosis, angiogenesis and restenosis after angioplasty.

BACKGROUND OF THE INVENTION

Similar compounds are known from Pharmacia 40 (8), 532-535 (1985).

SUMMARY OF THE INVENTION

The present invention provides cyclopeptides of formula (I) cyclo- (A-B-C-D-Arg) (I) wherein:

A and B are each independently Ala. Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val,

C represents Asp or Asp (O-C _1-4 alkyl) and

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

It has been found that the compounds of formula (I) and their salts have very valuable properties. In particular, these compounds act as inhibitors, suppressing in particular the interaction of β ₃ -integrin receptors with ligands. This effect can be demonstrated, for example, by the method of JW 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 medicine, in particular for the prophylaxis and treatment of circulatory diseases, thrombosis, heart attack, arteriosclerosis, inflammation, apoplexy, angina pectoris, malignant tumors and osteolytic diseases, in particular osteoporosis and restenosis. after angioplasty.

The following abbreviations of the amino acid esters for the residues of the following amino acids are used in the foregoing and following: Ala alanine

Asp asparagine

Asp (OR) aspartic acid (-ester)

Arg arginine

Cys cysteine

Gin glutamine

Glu glutamic acid

Gly glycine

His histidine white isoleucine

Leu leucine

Lys lysine

Met methionine

Phe phenylalanine

For proline

Ser serín

Thr threonine

Trp tryptophan

Tyr tyrosine

Val valín.

Further abbreviations are used which mean: BOC tert-butoxycarbonyl

CBZ benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

MDF dimethylformamide

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

Et ethyl

FMOC 9-fluorenylmethoxycarbonyl

HOBt 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.

When said amino acids may have a plurality of enantiomeric forms, all of these forms as well as mixtures (e.g., DL-forms) are encompassed above and in the following. for example as part of a compound of formula (I).

The present invention further provides a process for the preparation of the compounds of formula (I) mentioned above or salts thereof, which comprises releasing from their functional derivative by treatment with a solvolyzing or hydrolyzing agent, or by treating a peptide of formula (II).

H-Z-OH (II) wherein

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

-BCD-Arg-A-, -CD-Arg-AB-, -D-Arg-ABC- or -Arg-ABCD, or a reactive derivative of such a peptide is treated with a cyclizing agent and / or a basic or acidic compound of the general formula (I) transforms it by treatment with an acid or base into its salt.

In the foregoing and in the following, the radicals A, B, C, D and Z have the meanings given in the general 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. D is preferably Gly.

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

A preferred group of compounds may be represented by the partial formula (Ia), which otherwise corresponds to the general formula (I), but in which A represents D-Val, B represents Phe, C represents Asp and D represents Gly or Ala.

The compounds of 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-Thieme-Verlag, Stuttgart) and 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 immediately to react to the compounds of formula (I).

The compounds of general formula (I) may be obtained when released from their functional derivatives by solvolysis, in particular by hydrolysis or hydrogenolysis.

Preferred starting compounds for solvolysis or hydrogenolysis 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 carry 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 at the place of the hydrogen atom of the hydroxy group, for example those which correspond to the general formula (1) but instead of the hydroxyphenyl group contain a RO-phenyl group, wherein R is a hydroxy protecting group.

Also, several identical or different protected amino and / or hydroxy groups may 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 are suitable for protecting (blocking) the amino group from chemical reactions, but which are readily cleavable when the desired reaction elsewhere in the molecule is carried out. Typically, such groups are unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are cleaved after the desired reaction (or sequence of reactions), their type and size are not critical. Preferably, however, there are groups having 1 to 20, and in particular 1 to 8, carbon atoms. As used herein, the term acyl is always understood in its broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl 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 are BOC and Mtr, CBZ, benzyl and acetyl.

The term hydroxy protecting group is generally known and refers to groups which are suitable for protecting the hydroxy group from chemical reactions but which are readily cleavable when the desired reaction at another site in the molecule is carried out. Typical such groups are unsubstituted or substituted acyl, aryl or aralkyl groups, and also alkyl groups. The nature and size of the hydroxy protecting groups is not critical, since the hydroxy protecting group is cleaved off after the desired reaction, 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 the benzyl and acetyl groups 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) J.

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 described in the basic works and patent applications, for example by the Merrifield solid phase method (BF Gysin and RB Merrifield, J. Am. Chem. Soc. 94, 3102 (1992).

The release of the compounds of formula (1) from their functional derivatives is carried out depending on the functional group used, for example by treatment with strong acids such as trifluoroacetic acid and perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, strong organic carboxylic acids. 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 (THF) or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols, such as methanol, ethanol or isopropanol as well as water. Mixtures of these solvents may also be suitable. Trifluoroacetic acid is preferably used in excess without the addition of an additional solvent, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is suitably about 0 to about 50 ° C, preferably 15 to 30 ° C (room temperature).

The BOC, OBut and Mtr groups can be conveniently cleaved by treatment with trifluoroacetic acid in dichloromethane or by treatment with 3- to 5-normal hydrochloric acid in dioxane at a temperature of 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 from 15 to 30 ° C.

Hydrogenolytically cleavable protecting groups (e.g., CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as coal). Suitable solvents are the solvents mentioned, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group, for example, performs well on 5-10% palladium on carbon in methanol, or by treatment with ammonium formate at 20-30 ° C.

Compounds of formula (I) may be obtained by cyclization of compounds of formula (II) under conditions for peptide synthesis. This is conveniently done by conventional methods known for peptide synthesis, such as those described in Houben-Weyl, cited vol. 15/11, p. 1 to 806 (1974).

The reaction is preferably carried out in the presence of a dehydrating agent, a carbodiimide such as DCCI or EDCI, propanephosphonic anhydride (cf. Angew. Chem., 92, 129, 1980), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2,2 a dihydroquinoline, in an inert solvent such as a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as dimethylformamide or dimethylacetamide, a nitrile 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 can also be used in the reaction, for example those in which the reactive groups are intermediately blocked by protecting groups. The amino acid derivatives of the formula (II) can be used, for example, in the form of their activated esters which are conveniently formed in situ, for example by the addition of HOBt or N-hydroxysuccinimide.

The starting compounds of the general formula (II) are usually novel compounds which can be prepared by known methods, for example methods described for peptide synthesis and cleavage of protecting groups.

In particular, a protected pentapeptide ester of the general formula R'-ZR, for example BOC-Z-OMe or BOC-Z-OEt, is first synthesized and is first saponified to an acid of the general formula R'-Z-OH, for example BOC-R-OH and of this compound, the R 'protecting group is cleaved to give the free peptides of formula (II)

H-Z-OH (II).

The base of formula (I) may be converted by reaction 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, organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic acids can be used. monohydric or polybasic carboxylic, sulfonic or sulfuric acids such as formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, benzoic, salicylic or 3-phenylpropionic acids , citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic, ethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic and naphthalenedisulfonic acid, and lauryl sulfonic acid. Salts with acids that are not physiologically innocuous, for example picrates, can be used to isolate and / or purify the compounds of formula (I).

On the other hand, the acid of formula (I) can be converted into its physiologically acceptable salts by metal or ammonium reaction with a base. Suitable salts here are the sodium, potassium, magnesium, calcium and ammonium salts, further substituted ammonium salts, e.g. -methyl-D-glucamine or with arginine or lysine.

The novel compounds of formula (I) and their physiologically acceptable salts can be used in the manufacture of pharmaceutical compositions by contacting them in a suitable dosage form with at least one carrier or excipient and at least one other substance. The compositions thus obtained can be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral or rectal), parenteral (e.g. intravenous injection) or topical (e.g. topical, dermal, ophthalmic or nasal) applications or for use as inhalation sprays and with novel compounds not reacting, such as water, aqueous isotonic sodium chloride solutions, lower alcohols, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, and other glycerides of fatty acids, gelatin, soy lecithin, carbohydrates such as lactose or starches, magnesium stearate, talc, and petroleum jelly. Especially suitable for oral use are tablets, dragees, capsules, syrups, juices or drops, of particular interest being lacquered tablets and capsules with gastric juice-resistant coatings or coated capsules. Suppositories are used for rectal administration, solutions, in particular oily or aqueous solutions, as well as suspensions, emulsions or implants, are used for parenteral administration. Suitable for topical use are, for example, solutions which are used in the form of eye drops, for example, suspensions, emulsions, ointments, creams 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 in this case effectively used in micronized form, whereby one or more additional physiologically compatible solvents such as ethanol can be added. Inhalable solutions may be administered using conventional inhalers. The novel compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the preparation of injectables. The injections may be administered as a bolus or continuous infusion (e.g. intravenous, intravascular, subcutaneous or intrathecal). Said compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizing agents and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, and / or flavoring agents. The compositions may, if desired, also contain at least one further active ingredient, for example one or more vitamins.

As a rule, the compounds of the invention can be administered analogously to known commercially available peptides, in particular as described in U.S. Pat. No. 4,472,305, preferably at doses of from about 0.05 to 500 mg, in particular from 0 to 500 mg. 5 to 100 mg per dosage unit. The daily dose is preferably from about 0.01 to 2 mg / kg body weight. The dose for each individual patient will depend on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, elimination rate, drug combination and severity of the disease. . Oral administration is preferred.

The invention is illustrated by the following non-limiting examples. Temperatures are given, as is usual, in degrees Celsius. Conventional work-up in the following examples illustrates: Optionally water is added, neutralized, extracted with ether or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, evaporated and purified 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 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 FAB (fast atom bombardment) technique.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 30 mg of cyclo- (D-Val-L-Phe-D-Asp (OBut) -Gly-D-Arg (Mtr)) (which can be obtained by cyclization of HD-Arg (Mtr) -D-Val-L-Phe The -D-Asp (OBut) -Gly-OH by the method of Example 2) in 840 µl TFA, 170 µl dichloromethane and 85 µl 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. Gel filtration using Sephadex G 10 in 1: 1 acetic acid / water, followed by high performance liquid chromatography on a column packed with LiChrosorb RP 8 with an isopropanol gradient in 0.3% TFA in water gave the cyclo- (D-Val). -L-Phe-D-Asp-Gly-D-Arg), RD 17.9, M ⁺ 575.

In an analogous manner there is obtained: zyclo- (D-Val-D-Phe-D-Asp (OBut) -Gly-D-Arg (Mtr)) cyclo- (D-Val-D-Phe-D-Asp-Gly-D) -Arg), RD 18.5, M ⁺ 575;

from cyclo- (D-Val-D-Phe-L-Asp (OBut) -Gly-D-Arg (Mtr)) cyclo- (D-Val-D-Phe-L-Asp-Gly-D-Arg), RD 19.3, M ⁺ 575;

from cyclo- (DV a1-D-Phe-D-Asp (OBut) -L-Ala-D-Arg (Mtr)) cyclo- (D-Val-D-Phe-D-Asp-L-Ala-D-) Arg), RD 20.3, M ⁺ 589;

zcyclo- (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, M ⁺ 589;

from cyclo- (D-Val-D-Phe-L-Asp (OBut) -Gly-L-Arg (Mtr)) cyclo- (D-Val-D-Phe-L-Asp-Gly-L-Arg);

from cyclo- (L-Val-D-Phe-D-Asp (OBut) -Gly-L-Arg (Mtr)) cyclo- (L-Val-D-Phe-D-Asp-Gly-L-Arg);

from cyclo- (D-Val-L-Phe-D-Asp (OBut) -Gly-L-Arg (Mtr)) 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-Gly-D-Arg);

from cyclo- (D-Val-L-Phe-L-Asp (OBut) -Gly-D-Arg (Mtr)) cyclo- (D-Val-L-Phe-L-Asp-Gly-D-Arg);

from cyclo- (L-Val-L-Phe-D-Asp (OBut) -Gly-D-Arg (Mtr)) cyclo- (L-Val-L-Phe-D-Asp-Gly-D-Arg);

from cyclo- (L-Val-D-Phe-L-Asp (OBut) -D-Ala-L-Arg (Mtr)) cyclo- (L-Val-D-Phe-L-Asp-D-Ala-L) -Arg);

zcyclo- (D-Val-L-Phe-L-Asp (OBut) -D-Ala-L-Arg (Mtr)) -cyclo- (D-Val-L-Phe-L-Asp-D-Ala-L- arg);

zcyclo- (L-Val-L-Phe-D-Asp-OB-OB-OB-D-Ala-L-Arg (Mtr)) Arg) and cyclopropyl (L-Val-L-Phe-L-Asp (OBut) -D-Ala-D-Arg (Mtr)) cyclo- (L-Val-L-Phe-L-Asp-D-Ala) D-Arg).

Example 2

Solution 80 mg HL-Arg-D-Val-D-Phe-D-Asp (OMe) -Gly-ONa (which can be obtained by cleavage of the FMOC group from FMOC-L-Arg-D-Val-D-Asp (OMe) -Gly-O-Wang, where O-Wang is a 4-oxymethylphenoxymethyl polystyrene residue used in Merrifield synthesis, crosslinked from 1% p-divinylbenzene, by treatment with morpholine and cleavage of the pentapeptide from the polymer by treatment with a mixture of TFA and dichloromethane. After drying with a solid carbon dioxide / acetone mixture, 34 µl of diphenylphosphoryl azide are added, the mixture is left to stand at 20 ° C for 16 hours and then distilled off at 37 ° C with dichloromethane, and the remaining solution is subjected to gel filtration ( on a Sephadex G10 column with an 8: 2 mixture of isopropanol and water) and then subjected to a polymer column chromatography (Mitsubishi MCI CNP-20P) using an isopropanol gradient in water to give the cyclo- (D-Val-D-). Phe-D-Asp (OMe) -Gly-L-Arg), 21.4, M ⁺ 589.

Pharmacological tests

The compounds of the invention were tested in their ability to inhibit the binding of certain ligands to the A, B and _R ^ Bj-rcceptory.

The assays were performed according to the method described by L. W. Smith et al. in J. Biol. Chem., 265, 1267-12271 (1990).

M ⁺ 4 1 (FAB) / RT (LUN) (2PLC) sequence Ex. Pamacological values of IC ₅₀ (μκak / ΐ) Koncantr. rosmdaie

0.001 * 5 μβοί

Wipe

575 / 18.5 cyclo-1D-Vel-D-Phe-D-Aap-Gly-D-Arg <0.001 5 575 / 19.3 cyclo- (D-Vel-D-Fhe-Aap-Gly-D-Arg) 1 0,2 5 589 / 20.3 cyclo-D-V-L-D-Phe-D-A-p-Hla-O-Arg) 1 2,5 5 589 / 21.4 Cyclo- (D-Vel-D-Phe-D-Aep (CWe) -Gly-Arg) 2 0,02 5 575 / 17.9 cyclo-D-Vil-Phe-D-X-p-Gly-Arg 0,2 5

abbreviations:

RT retention time (HPLC)

FGN ajfi a fibrinogen-receptors (isolated) _a-b fi aiibBj ₃ receptor (isolated)

The test results demonstrate the inhibitory effects of the compounds of this invention on integrins. The observed effect shows that the compounds are capable of inhibiting the binding of α 1 - and α 1 -receptors. Thus, for example, the compounds of the invention are useful for inhibiting osteoclast adhesion to bone and therefore bone catabolism. In addition, the inhibitory effect is very important in the treatment of angiogenesis, thrombosis, malignant tumors, especially tumor growth and other diseases described. All these diseases are promoted by the adhesion of certain cells and can be treated by effective inhibition of adhesion.

The examples below relate to pharmaceutical compositions.

Example A

Injection vials

A solution of 100 g of the cyclopeptide of formula I and 5 g of sodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered, vialed, lyophilized under sterile conditions and sterile is sealed. Each vial contains 5 mg of active substance.

Example B

suppository

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

Example C

solution

A solution of 1 g of an active compound of the formula I, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of dibasic sodium phosphate dodecahydrate and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH is adjusted to 6.8, the solution is made up to 1 liter and sterilized by irradiation. 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 with 99.5 g of petroleum jelly under aseptic conditions.

Example E

tablets

A mixture of 100 g of the cyclopeptide of formula (I), 1 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. of the active substance.

Example F

dragee

Similar to Example E, tablets are compressed and coated in a known manner with a coating of sucrose, corn starch, talc, tragacanth and dye.

Example G

The capsules

In a conventional manner, hard gelatine 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

14 g of the active compound of the formula I are dissolved in 10 liters of isotonic sodium chloride solution and the solution is filled into commercially available spray containers with a pump mechanism. The solution may be sprayed into the mouth or nose. Each injection volume (about 0.1 ml) corresponds to a dose of about 0.14 mg of active ingredient.

Claims (9)

Cyclopeptides of general formula (I) cyclo- (A-B-C-D-Arg) (I), in which: A and B are each independently Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val, C represents Asp or Asp (OC _M alkyl); D is Gly or Ala, wherein at least two of said amino acid residues are in D-form as well as salts thereof. A cyclopeptide according to claim 1 which is cyclo- (D- -Alpha-L-Phe-D-Asp-Gly-D-Arg). A cyclopeptide according to claim 1, which is cyclo- (D-Val-D-Phe-D-Asp-Gly-L-Arg). A cyclopeptide according to claim 1 which is cyclo- (D-Val-D-Phe-L-Asp-Gly-D-Arg). 5. The cyclopeptide of claim 1 which is cyclo- (D-Val-D-Phe-D-Asp-L-Ala-D-Arg). 6. The cyclopeptide of claim 1 which is cyclo- (D-Val-D-Phe-D-Asp (OMe) -Gly-L-Arg). A process for the preparation of compounds of formula (I) according to claim 1, wherein A and B are each independently Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val, C represents Asp or Asp (OC _M alkyl); D is Gly or ala, or a salt thereof, characterized in that they are released from their functional derivative by treatment with a solvolyzing or hydrolyzing agent, or by a peptide of formula (II) H-Z-OH (II) wherein Z is A-B-C-D-Arg-, -BCD-Arg-A-, -CD-Arg-AB-, -D-Arg-ABC- or -Arg-ABCD, or a reactive derivative of such a peptide is treated with a cyclizing agent and / or a basic or acidic compound of the general formula (I) transforms it by treatment with an acid or base into its salt. A pharmaceutical composition for the prophylaxis and treatment of circulatory diseases, thrombosis, heart attack, arteriosclerosis, inflammation, apolexia, angina pectoris, malignancies, osteolytic diseases, especially osteoporosis, angiogenesis and restenosis after angioplasty, comprising at least one compound comprising: of the formula (1) according to claims 1 and / or a physiologically acceptable salt thereof. Use of compounds of formula (I) according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament for the prophylaxis and treatment of circulatory diseases, thrombosis, heart attack, arteriosclerosis, inflammation, apolexia, angina pectoric, malignancies, osteolytic diseases, especially osteoporosis, angiogenesis and restenosis after angioplasty.