SK38494A3 - Linear adhesive inhibitors - Google Patents

Abstract

The invention relates to linear peptides of the formula I X-A-B-C-Arg-E-G-L-Z I, in which A, B, C, E, G, L, X and Z have the meaning stated in Claim 1, and the salts thereof. These compounds act as integrin inhibitors and can be used in particular for the prophylaxis and treatment of circulatory disorders and in tumour therapy.

Description

Linear adhesion inhibitors

Technical field

The invention relates to novel linear peptides of formula I

X - A - B - C - Arg - E - G - L - Z (C) wherein

X is H, C 1 -C 10 acyl, H-Asn, H-Val-Asn, K-Asp-Val-Asn-, Fmoc-Gl-y-Gly, H-Lys-Glv-Gly, H-Lys -Pro, HT, γ-Gly-Gly, H-Cys-Gly-Gly, H-Cys (Trt) -Glv-Gly, H-Cys-Gly-Gly-Thr-Asp-Val-Asn or H-Thr- Asp-Val-Asn,

A, B and C are not always present or are independently an amino acid residue selected from the group consisting of Ala, Arg, Asn, Asp (OR), Lys, Gln, Glu, Glv, Lis, Cle, Leu, Lys , Lvs (Ac), Lys (AcNH 4),)

L.vs (AcSH), Het, Orn, Phe, 4-Hal-Phe, Pro, Ser, Thr, Trp, or Val, wherein said amino acid rings may also be derivatized,

E is Gly, His or Leu-His,

G is absent or is Asp or Asn,

L is missing or means Gly, Ile, Leu or Leu-Leu,

Z is HH ₂ or OH,

Hal represents P, Cl, Br, 1a

Ac is C 1 -C 10 -alkynoyl as well as physiologically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Similar compounds are known, for example, from European patent application EP 0406426.

The invention solves the task of finding novel compounds with valuable properties, in particular those which can be used for the manufacture of medicaments.

SUMMARY OF THE INVENTION

The compounds of formula L and their salts have been found to possess valuable properties. In particular, they act as integrin inhibitors, in particular by inhibiting the interaction of β-β-integrin-β-ceptors and ligands. This efficacy can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990) All have anti-inflammatory effects. This efficacy can also be demonstrated by methods known in the literature.

The compounds can be used as active substances in medicaments in human and veterinary medicine, in particular for the prophylaxis and treatment of circulatory diseases, thrombosis, heart attack, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumors, osteolytic diseases, in particular osteoporosis, angiogenesis and restenosis angiogenesis and restenosis i. however, the compounds may be used to improve bed sores.

In addition, the compounds are useful as natimicrobial active substances which can prevent infections such as infections caused by bacteria, fungi or yeasts. The substances may advantageously be used as concomitant antimicrobial active substances, in an intervention in the body using foreign substances such as biomaterials, implants, catheters or cardiac stimulators. They act as antiseptics.

Previously, the amino acid residue abbreviations below represent the following amino acid residues:

Ala alanine Arg arginine same time asparsgín Asp aspartic acid Asp (OP) (β-ester) aspartic acid C i t citr citrulline Cys cysteine Dab 2,4-diamino-butyric acid gin glutamine Glu glutamic acid GLV gl.vcín E i s h istidír. Ile isoleucine Leu leucine Lv s lv zín Lys (Ac) N, N-acyl LystAcEE (N) -N-aminoacyllysine L, y s (A cSH) N-mercaptoacyllysine flight met ionine Orn ornithine Phe phenylalanine 4-Hal · -Phe 4-halophenvlalanine for proline Ser serine Thr threonine Trp tryptophan Tyr tyrosine wall valine.

Calej means:

BOC t-butoxycarbonyl

CBZ benzyloxycarbones1

ECCI 6-cyclohexylcarbodiimide

LMF dimethylforinamide

ECI]] - ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride

Et ethyl

Emotion of 9-fluorenylmethoxycarbonyl

HOBt 1-hydroxybenzotriszolithiethyl BH A 4-methylbutyric amine 4-methoxy-2,3,6-trimethylphenylsulfonyl

Obut terc.butylester

Olie metvlester

OEt ethyl ester

BOA fenoxvscetyl

TEA trifluoroacetic acid

Trt trityl (triphenylmethyl).

As the above-mentioned amino acids may exis ^J ovata ioinérnych enantiomorphs in a number of forms, as in the previously mentioned and further, e.g. as part of a compound of formula I, all these forms as well as mixtures thereof (e.g. DL-forms) are included. In addition, the amino acids or the the amino acid residues may be of known derivatized form.

The invention further provides a process for the preparation of the compounds of the formula I according to claim 1 or salts thereof, characterized in that such a compound is released from its functional derivative by treatment with a solvolyzing or hydrogenolyzing agent or by a peptide of the formula II.

M-OI (II)

- b where

M is (a) X, but not hydrogen, Emoc-Gly, K-Lys-Gly, HL-s, H-Tyr-Gly, H-Asp-Val, Η-Tyr, H-Val, H-Asp, H -Cys-Gly-Gly-Thr-Asp-Val, H-Cys-Gly-Gly-Thr, H-Cys-Gly-Gly-Hly, H-Cys-Gly-Gly, H-Cys-Gly-Hly , Η-Cys, H-Cys (Trt) -Gly, H-Cys (Trt), H-Thr-Asp-Val, H-Thr-Asp, or H-Thr, (b) XA, (c) XAB, ( (d) XABC, (e) XABC-Arg, (f) XABC-Arg-E, or (g) XABC-Arg-EG, reacted with an amino compound of formula IIT.

HQZ (III) wherein Z is as defined above and Q is (a) ABC-Arg-EGL, Asn-ABC-Arg-EGL Val-Asn-ABC-Arg-EGL, Pro-ABC-Arg-EGL, Gly-ABC- Arg-EGL, Gly-Gly-ABC-Arg-EGL, Asp-Val-Asn-ABC-Arg-EGL, Asn-ABC-Arg-EGL, Thr-Asp-Val- Asn-ABC-Arg-EC-L, Gly-Thr-Asp-Val-Asn-ABC-Arg-EGL or Gly-Gly-Thr-Asp-Val-Asn-ABC-Arg-EGL, (b) BC-Arg -EGL, (c) C-Arg-EGL, (d) Arg-EGL, (e) EGL, (f) GL or (g) L, and / or that the free amino group, if any, is acylated and / or the compound of formula I is converted to its salt by treatment with an acid or base.

The residues A, B, C, E, G, L, M, Q,

X and Z have the meanings given in formulas i, I i and I CZ unless otherwise indicated.

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

X is preferably hydrogen, E-Asn, Fmoc-Gly-Gly or H-Cys (Trt) -Glv-Gly, particularly preferably H-Cys-Gly-Gly. Further, X can also be acyl of 1 to 10 carbon atoms, wherein acyl is preferably 1 to 1, especially 1, 2, 3 or 4, carbon atoms, especially preferably methyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl or hex. anoyl, but also aryl-CO, such as e.g. benzyl, o-, m- or p-toluyl, o-, m- or p-methoxybenzoyl as well as 2-naphthoyl or also aryl-C 2 _H -CO (n = 1-4) such as e.g. Ph-CH ₂ -CO, Ph (CH ₂ ) ₂ -CO, Ph-CH 2 CO 2 or Ph- (CH ₂ CH ₂ -CO (Ph = phenyl), where Ph can also be substituted with OCH 2 - or CH 2 -). -.

The group A is preferably Ala, Leu, Ser, in particular Gly or absent. B is preferably Asn or Asp. C is preferably Ala, also L-Ala, His and especially Gly. E is preferably Gly or His. G is preferably Asp, while L is preferably Leu. Z is NH ₂ , but particularly preferably OH.

Accordingly, the present invention is particularly directed to those compounds of the general formula [wherein at least one of said radicals has one of the preferred meanings indicated.

A preferred group of compounds may be represented by the formula Ia, which corresponds to the formula I s wherein B, C, E, X and Z are as defined herein and

And it means Gly,

G is Asp s

L stands for Leu.

Other groups of preferred compounds may be represented by the partial formulas Eaa to ice, which correspond, however, to formula (E) or (E). la, where, however

in lea: X means hydrogen or acet A means Gly, B means Asn or Asn, C a mistake, means But or E means Gly or I’is, G means Asp, L means Leu a r? IN means ISB: NH 'or OH, x means hydrogen or acyl A means Gly or missing B means Asn or missing C means Gly, n means Gly or His, G means Asp, L means Leu a FROM znarnc-Na KH ₂ or OH,

in Iec:

ABOUT ' Λ means v od í k A znsmená Gly or a mistake B means Asn or a mistake C means t> lv or a mistake TO means Gly or His G means Asp L means Leu a FROM means OH or nh ₂ ,

in Isó:

X is Η-Asn, H-Val-Asn, H-Asp-Val-As, Em-Gly-Gly, H-Lys-Glv-Gly, II-Tyr-Glv-Gly, H-Cys (Trt) -Gly -Gl.y, H-Cys-Gly-Gly, H-Cys-Gly-Gly-Thr-Asp-Val-Asn or H-Thr-Asp-Vsl-Asn,

And means ^u ly,

B asn,

C is Gly,

E means Gly discount His,

G stands for Asp,

L is Leu and

Z is NH ₂ OH slebo.

Particularly preferred are those compounds which correspond to the formula I and wherein A, B, C, X and Z have the above-mentioned preferred meanings, but where the central amino acid residue is L-Arg, not L-Arg, E denoted by Glv as sj His, not D-His, G is Asp with L Leu.

The compounds of the formula I as well as the starting materials for their preparation can generally be prepared according to known methods as described in the literature (e.g. in standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgard), under the reaction conditions known and suitable for the above reactions.

In this case, it is also possible to proceed according to known process variants which are not mentioned in more detail here.

The starting materials can, if desired, also be formed in situ so that they are not isolated from the reaction mixture, but are reacted to other compounds of formula I directly.

Compounds of formula T may be obtained by liberating from their functional derivatives by solvolysis, in particular by hydrolysis, or hydrogenolysis.

Preferred starting materials for solvolysis, respectively. hydrogenolysis are those which contain, instead of one or more free amino and / or hydroxy groups, the corresponding protected amino and / or hydroxy groups, preferably those which, instead of the H-atom which is linked to the H-atom, carry an amino-protecting group, e.g. those that match the formula. I but instead of an _NH2 group contain NHR'-(wherein R is an amino protecting group, e.g. BOC or CBZ).

Further preferred are those starting materials which carry a protecting group instead of the H-atom of the hydroxy group, e.g. those corresponding to formula (I), but instead of the hydroxyphenyl group, contain a RO-phenyl group (where R is a hydroxy protecting group).

Multiple - identical or different - protected amino and / or hydroxy groups may also be present in the molecule. In the event that the aforementioned protecting groups differ from one another, they may in many cases be selectively cleaved.

The term amino protecting group is generally known and refers to groups which are suitable to protect the amino group from (chemical blocking) reactions, but which are readily removable after the desired chemical reaction has been carried out at other sites in the molecule. Typically, such groups are in particular unsubstituted or substituted acyl, N-aralkoxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are generally not critical; Preference is given to groups having 1 to 20, in particular 1 to 6 carbon atoms. The term ac.-group is understood in a broader sense in the context of the above method and the present compounds. It includes aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids introduced by acyl groups, and in particular alkoxycarbonyl, arvloxycarbonyl and in particular aralkoxycarbonyl groups. Examples of such groups are slkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as m-toxiccarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, aralkyloxycarbonyl such as CBZ (carbobenzoxy), 4-methoxybenzyloxycarbonyl, FmOC; arlsulfonyl such as Mtr. Preferred protecting groups are BOC and Mtr, targets are CBZ, Fmoc, benzyl and acetyl.

The term hydroxy protecting group is also generally known and refers to groups which are suitable for protecting the hydroxy group from chemical reactions but which are readily removable after the desired reaction has taken place elsewhere in the molecule. Such typical 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 they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10 carbon atoms. Examples of hydroxy protecting groups are the orir of another benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred. The COOH groups in aspartic acid and glut amine acid are preferably protected in the form of their tert-butyl ester (e.g. Asp (OBut)).

The functional derivatives of the compounds of formula (I) used as starting materials may be prepared by conventional methods of synthesis of amino acids and peptides, such as e.g. described in the aforementioned standard works and patent applications, e.g. also by the solid phase method of I.errifield (B. P. Gysin and P. B. Merifield, J. Am. Chem. Soc. 94, 310ff. (1972)).

Release of compounds of formula I from. their functional derivatives thrive - depending on the protecting group used, e.g. with strong acids, preferably with TPA or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of some other inert solvent is possible but not always necessary. Suitable inert solvents are in particular organic, for example, carboxylic acids such as acetic acid, an ether such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol as well as water. Mixtures of the abovementioned solvents are furthermore possible. TPA is preferably used in excess without the addition of an additional solvent such as perchloric acid in the form of a 9: 1 mixture of acetic acid and 10% perchloric acid. The reaction temperatures of the cleavage are suitably between about 0 and about 90 ° C, preferably between 1 and 30 ° C (room temperature).

The BOC, OBut and Etr groups can be cleaved, e.g. preferably with TFA in dichloromethane or about 3 to 5N KCl in dioxane at 15 to 30 ° C, an Fmoc group of about 5 to 50% solution of dimethylamine, diethylamine or poperidine at 15 to 30 ° C in DMF.

Cydrogenolvtically removable protecting groups (e.g. CBZ or benzyl) may be e.g. cleaved by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably the carrier is coal). Suitable solvents for this purpose are the abovementioned solvents, in particular non-solvent. alcohols such as methanol or ethanol or amides such as DEF. Cydrogenolysis is generally carried out at temperatures between 9 and 100 ° C and a pressure of about 0.1 to 20 MPa, preferably at 20 to 30 ° C and 0.1 to 1 Mpa. Cydrogenolysis of the CBZ group thrives well at 5 to 10% Pd-C in methanol or ammonium formate (instead of Pd-C in motanol / DEF at 20-30 ° C).

Compounds of formula I may also be obtained by reacting a compound of formula II with an amino compound of formula IEI after. of known peptide synthesis condensation conditions, such as e.g. described in Kouben-V / eyl,

L C. 1-5 / .ΙΓ, p. 1-606 (1974).

The reaction proceeds preferably in the presence of a dehydrating agent, e.g. carbodiimide such as ICC or ELC targets of propanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphorvlazide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solution. a solvent, e.g. a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as IMF or dimethylacetamide, nitrile such as acetonitrile, or mixtures of these solvents, at temperatures between about -10 and 40, preferably between 0 and 30 ° C.

Instead of the compounds of formula II, suitable reaction-capable derivatives of these compounds, e.g. those in which the reactive groups are intermediately blocked by protecting groups. For example, the amino acid derivatives of the formula II can be used in the form of their active esters which are conveniently formed in situ, e.g. by adding HOBt or N-hydroxysuccinimide.

The starting materials of formula II are usually new. However, they can be prepared by methods known per se, e.g. by the above methods of peptide synthesis and cleavage of protecting groups.

Usually, a protected peptides ester of the formula r'-M'-OR is synthesized first, where M corresponds to the residue M at the N-terminal end reduced by one H-atom, e.g. BOC-M -OMe or Fmoc-M -OMe. These are saponified to acids of the formula R-Li-OH, e.g. BOC-M'-OH or Fmoc-M -OH and then condensed with a compound of formula III, which, if desired, is provided with appropriate protecting groups at positions not intended to be accessible to the reaction.

In the case of compounds of formula III, the peptides ester of formula R-Q-Z'-R, such as e.g. BOC-Q-Z'-OMe or Fmoc-Q-Z'-OMe, wherein Z'-NE- or -O means and then is cleaved before condensation is carried out to produce compounds of formula I protecting the R group by known R way, nspr. Fmoc by spraying with piperidine / LMP solution.

Particularly advantageously, there may be found use of a more recent pc-ptide synthesis method according to modified Perrifield techniques using peptide synthesis devices such as not; r. described in Peptides, Proc. 8th Am Pept. Symp., Fd. V. Hruby n L. H. Pich, Pierce Comp. TIE, p. 73-77 (1963) by A.Jonczyk and J.Maienhofer (Fmoc-strategy) or techniques listed in Angew.Chem. 104: 375-391 (1992). Similar methods are known per se and their description is not necessary here.

The base of formula (E) can be converted by an acid to the corresponding acid addition salt. Suitable acids for this conversion are, in particular, those which give physiologically acceptable salts. Thus, inorganic acids, e.g. sulfuric acid, nitric acid, hydrohalogenic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acids, further organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. 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, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid mono and disulfonic acid. Salts with physiologically unacceptable salts

- 15 acids, e.g. picrates may be used to isolate and / or purify the compounds of formula I.

In the second harness, the acids of formula I can be converted into their physiologically acceptable metal salts or ammonium salts by reaction with a base. Suitable salts here are, in particular, the sodium, potassium, magnesium, calcium salts of ammonium, further substituted ammonium salts, e.g. dimethyl-, diethyl- or diisopropvlammonium salt, mono-ethnol-, diethanol- or triethanoammonium salts, cyclohexyl-, dicyclohexylammonium salts, dibenzylethylenediammonium salts, alc-e.g. salts with N-methyl-D-glucamine or arginine or lysine.

Furthermore, the novel compounds of formula t can be used as integrin ligands for the production of affinity chromatography columns for integrin purification.

Ligand, ie. the peptide derivative of formula (I) is attached via a functional group to the polymeric carrier.

Suitable polymeric carrier materials are those known in the chemistry of peptides as polymeric solid phases with preferably hydrophilic properties, for example cross-linked polycarbohydrates such as cellulose, Sepharose or Sepha.

R dex acrylamide, polymers based on polyethylene glycol or p

Tentakelpolymere.

Linear alkylene chains of 2 to 12 carbon atoms which are attached at one end to the polymer and the other end of which has a functional group such as e.g. hydroxy, amino, mercapto, maleimido or -COOH and are suitable to combine with C- or

N-terminal portion of each peptide.

It is possible for the peptide to be bonded directly or optionally via a second exchange functional group to a polymer exchange group. Furthermore, it is possible that peptides that contain amino acid residues with functionalized side chains will be linked through them to interchanging functional groups of the polymer.

Therefore, the determined amino acid residues that are part of the peptide of formula I can be so modified in their side chains that they can be used to anchor via e.g. SH-, OK-, Ή \ Ή ₂ ^β 1θβο COOH-groups of the exchange, functional polymer group.

Unusual amino acids such as e.g. phenylalanine derivatives which carry a mercapto-, hydroxy-, amino- or carboxy-alkyl chain at the 4-position of the phenyl ring, wherein the functional group is not terminated at the end of the chain.

Examples of amino acid residues whose side chain can directly serve as an exchange function are e.g. Lys, Orn, Arg, Bab, Asp, Asn, Glu, Ser, Thr, Cys, Cit, or Tyr.

Examples of the N-terminal functional group are residues such as e.g. -CO-C _n H _2n -WH _2, -CO-C _n H _2n -OH, -C 0 -C _n H _{2 n} -5 or-CO-C ₂ H _n-COOH with n = 2-12, the length of the alkylene chain is not critical and can also e.g. be partially or fully replaced by aryl- or alkylarylz.

C-terminal exchange functional groups can, for example, OC H ₉ SH, -OC Ho OH, OC H _a -WH, OC H _a n ¹ 2 n n 2 n n 2 n n 2 n

COOH. -NH-C H .. -SH, -NK-C H ₉ -OH, -NK-C H ₉ -NH ₉

-NH-C _n H _{2 n} -COOH, while felting both the n and the alkylene chain as mentioned in the previous paragraph.

N- with C-terminal exchange functional groups can also serve as an exchange functional component for an already functionalized side chain of an amino acid residue. There are, for example srninokyselinové radicals such as Lys (CO-C ₅ H _ig -xNH _2), -C AspGMH --COOH) or Cys (C; H-NH), the exchange function is always attached to a function group side chain.

The production of affinity chromatography materials is carried out under conditions which are common for the condensation of amino acids and have already been mentioned in the paragraph for the preparation of the compounds of the formula 1, respectively. in Pierce, Immuno Technology Catalog and Handbook (1990).

The novel compounds of formula I and their physiologically acceptable salts can be used in the manufacture of pharmaceutical preparations by bringing them into a suitable dosage form together with at least one carrier or excipient and, if desired, together with one or more other active ingredients. The preparations thus obtained can be used in human or veterinary medicine.

Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g., oral or cecal), parenteral (e.g., intravenous injection), or local (e.g., topical, dermal, ophthalmic or nasal) applications or in the form of an inhalation spray and do not react with the novel compounds, for example water or isotonic aqueous sodium chloride solution, lower alcohols, vegetable oils, benzyl alcohol, polyethylene glycol, glycerol triacetate, and other glycerides of fatty acids, gelatin, soy Ic citrate, magnesium stearate, talc, cellulose, petrolatum. For oral administration, in particular tablets, coated tablets, capsules, syrups, juices or drops; of interest are special lacquered tablets and capsules with gastric juice-resistant coatings or capsules. with such capsule shells. For rectal administration, suppositories serve, for parenteral administration, solutions, preferably oily or aqueous solutions, suspensions, emulsions or implants. For topical administration, e.g. solutions which can be used in the form of eye drops, e.g. suspensions, emulsions, creams, ointments or compresses. For applications as an inhalation spray, sprays containing the active ingredient may be used, either dissolved or suspended in a carrier gas or a carrier gas mixture (e.g., paraffin or fluorofluorocarbons or suitable substitutes). Suitably, the active ingredient is used in micronized form and one or more additional physiologically acceptable solvents may be added, e.g. ethanol. Inhalable solutions may be dispensed using conventional inhalers. The novel compounds may also be lyophilized and the lyophilizates thus obtained e.g. used to make injection preparations. injections may be given as a bolus or as a continuous infusion (e.g. intravenous, intramuscular, subcutaneous or intrathecal). Said compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers and / or crosslinkers, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colorants and / or flavorings. They may also, if desired, contain one or more other active substances, e.g. one or more vitamins.

The substances of the invention can usually be administered analogously to other known commercially available peptides, but particularly analogously to other compounds described in US-A.4472305, preferably at doses of about 0.05, especially between

- 19 0.5 s 100 mg ns dosage unit. The daily dose is preferably between about 0.01 and 2 mg / kg body weight. However, the specific dose for each particular patient depends on a variety of factors, such as the efficacy of the special compound employed, age, body weight, general health, sex, food, time of administration and route of administration, excretion rate, drug combination and difficulty. of the individual disease for which therapy is used. Parenteral administration is preferred.

Before and on, all temperatures are given in ° C.

In the following examples, the usual treatment means: if necessary, water is added, neutralized, extracted with ether or dichloromethane, separated, the organic phase is dried over sodium sulphate, filtered, evaporated and purified by silica gel chromatography and / or crystallization. R2 = retention time (minutes) by HPLC on Lichrosorb RP-select B (250-4.7 µm) -column, eluent: 0.3% TFA in water, isopropanol gradient from 0 to BO v / v; for 50 min. at 1 ml / min. Flux and detection at 215 "t" _from nm. M = molecular peak in the mass spectra obtained in the Growth Atom Bombardment Method (FAB), usually represents M + H, also by 1 weight unit increased in mass of each compound.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Dissolve 2.2 g of BOC-βsp-Gly-OH in a mixture of 150 ml of dichloromethane and 20 ml of DMF, cool to 0 ° C and then mix with 0.5 g of ECCI, 0.3 g of HOBt, 0.23 ml of N methyl-morpholine and 1 equivalent of H-Arg-His-Asp-Leu-OMe (both peptides are prepared by methods of modified field techniques). Stir for 20 hours at 0 ° C and 6 hours at room temperature. The reaction mixture is concentrated, treated with a mixed ion exchanger bed, and introduced into an aqueous HCl solution. The precipitated product is filtered off with suction and washed with water. Washing with ethyl acetate / petroleum ether gave BOC-Asp-Gly-Arg-His-Asp-Leu-OMe.

Analogously, it is obtained by condensing H-Arg-His-Asp-Leu-OBe with BOC-Gly-OH:

BOC-Gly-Arg-His-Asp-Leu-Ome, with BOC-Asn-Gly-Asp-Gly-OH:

BOC-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OMe, with BOC-Val-Asn-Gly-Asp-Gly-OB:

BOC-Val-Asn-Cly-As p-Gly-Arg-His-As p-Leu-OMe, with BOC-Asp-Vel-Asn-Gly-Asp-Gly-OH:

BOC-Asp-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OHe, with BQC-Lys-Gly-Gly-Gly-Asp-Gly-QH:

BOC-Lys-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Leu-OMe, with BOC-Tyr-Gly-Gly-Gly-Asp-Gly-OH:

BOC-Ty-Gly-Gly-Gl-y-As p-Gly-Arg-His-Asp-Lc-u-OBe, with BOC-Ala-Asp-Gly-OH:

BOC-Ala-As p-Gly-Arg-Hi s-As p-Leu-OMe, with BOC-D-Ala-Asp-Gly-OH:

BOC-D-Ala-Asp-Gly-Arg-His-Asp-Leu-Ome, with BOC-Gly-Asp-Ala-OH:

with BOC-Glv-Asp-Ala-Arg-His-Asp-Eeu-OKe, with BOC-Gly-1'-Asp-Gly-OH:

BOC-Gly-D-Asp-Gly-Arg-His-Asp-Leu-OMe, with BOC-Gly-Asp-1'-Ala-OH:

BOC-Gly-Asp-D-Ala-Arg-His-Asp-Leu-OMe, with BOC-Glv-Asp-OH:

BQC-Gly-Asp-Arg-Kis-Asp-Leu-OMe, with BOC-Cys (Trt) -G1, γ-Gly-Gl.y-Asp-OH:

BOC-Cys (Trt) -Gl, γ-Gly-Gly-Asp-Arg-His-Asp-Leu-Ome, with BOC-Cys-Gly-Gly-Glv-Asp-OH-OH:

BOC-Cys-Gly-Gly-Asp-Gl-Asp-Arg-His-Asp-Leu-OMe, with BOC-Cys (Trt) -Gly-Glv-Gly-Asp-Gl, v-QH:

BOC-Cys (Trt) -Gly-Gly-Gl, γ-Asp-Gly-Arg-His-Asp-Leu-OMe with BOC-Cys-Gly-Gly-Gly-Asp-Gly-OH:

BOC-Cys-Gly-Gly-Gly-Asp-Glv-Arg-His-Asp-Leu-OMe, with BOC-Cys-Gly-Gly-Thr-Asp-Vsl-Asn-Gly-Asp-Gly-OH: BOC -Cys-Gly-Gly-Thr-Asp-Vsl-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OMe, with BOC-Tbr-Asp-Val-Asn-Gly-Asp-Gly- OH:

BOC-Thr-Asp-Val-Asn-Gly-Asp-Gly-Arg-Kis-Asp-Leu-OMe.

Example 2

Analogously to Example 1, it is obtained by reacting BOC-Gly-Asp-Gly-OH with H-Arg-His-Asp-OMe:

BOC-Gly-Asp-Gly-Arg-His-Asp-OMe with E-Arg-Eis-OMe:

B O C - G1 y - A with p - G1 y - A r g - H i s - O M e, with H-Arg-Kis-Asn-Leu-OMe:

BOC-Gly-Asp-Gly-Arg-Eis-Asn-Leu-OMe, with K-Arg-Gly-Asp-Leu-OMe:

BOC-Gly-Asp-Gly-Arg-Gly-Asp-Leu-OMe, with H-Arg-His-D-Asp-Leu-OMe:

BOC-Gly-Asp-Gly-Arg-His-D-Asp-Leu-OMe, with H-Arg-1'-His-Asp-Leu-OMe:

BOC-Gly-Asp-Gly-Arg-1'-Hi s-Asp-Leu-OMe, with H-1'-Arg-His-Asp-Leu-OMe:

BOC-Gly-Asp-Gl-D-Arg-His-Asp-Leu-OMe.

Analogous to Example 1, by reaction of BOC-Gly-Asn-Gly-OH with H-Arg-His-Asn-Leu-OMe:

BOC-Gly-Asn-Glv-Arg-Kis-Asn-Leu-OMe, with H-Arg-His-Asp-Leu-OMe:

BOC-Gly-Asn-Glv-Arg-Hi-As-p-Leu-OMe.

Example 3

Analogous to Example 1, the reaction was carried out. obtained by condensation:

BOC-Leu-Asp-His-Arg-Oh with H-Gly-Asp-Gly-OEt:

BOC-Leu-Asp-His-Arg-Gly-Asp-Gly-OEt,

BOC-Lys-Gly-Gly-Gly-Asp-Arg-Leu-OH with H-His-Asp-Gly-OEt:

BOC-Lys-Gly-Gly-Gly-Asp-Arg-Leu-His-Asp-Gly-OEt,

BOC-Lys-Pro-Ser-Asp-OH with H-Gly-Arg-Gly-OEt:

BOC-Lys-Pro-Ser-Asp-Gly-Arg-Gly-OEt,

BOC-Arg-His-OH with H-Asp-Leu-OMe:

BOC-Arg-His-Asp-Leu-OMe,

BOC-L-Lys-L-Pro-D-Ser-C-Asp-L-Gly-OH with H-L-Arg-D-Gly-OMe BOC-E-Lys-L-Pro-L-Ser-B D-Asp-Gly-L-Arg-L-Gly-OMe

BOC-Leu-sp-His-OH with H-Arg-Gly-Asp-OMe:

BOC-Leu-As p-Hs-Arg-Glv-As p-OMe, bOC-Leu-Asp-His-OK p. H-Arg-Gl-y-OMe:

BOC-Leu-Asp-His-Arg-Gly-Phe-OMe,

BOC-Glv-Arg-His-OH with H-Asp-Leu-Leu-OMe:

SOC-Gly-Arg-His-Asp-Leu-Leu-OMe,

BOC-Arg-Gly-OH with H-Asp-Leu-OMe:

BOC-Arg-Gly-Asp-Leu-OMe,

BOC-Cys-Gly-Gly-Gly-Asp-Arg-OH with H-Leu-His-Gly-OMe:

BOC-Cys-Gly-Gly-Gly-Asp-Arg-Leu-Gly-PIS-OMe,

BOC-Cys-Gly-Gly-Gly-Asp-Gly-Arg-OH with H-His-Asp-Ile-OMe;

BOC-Cys-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Ile-OMe.

Example 4

Dissolve 1.3 g of BOC-Asp-Gly-Arg-His-Asp-Leu-OMe in 60 ml of methanol, mix with 1.5 ml of 2N NaOH solution and stir at 25 ° C for 4 hours. After removal of the solvent, the residue is taken up in water, the pH is adjusted to 3 by addition of dilute HCl and extracted with ethyl acetate. The extract was dried over Wa 2 SO 4. After removal of the solvent, BOC-Asp-Gly-Arg-His-Asp-Leu-OH was obtained, which was evaporated to dryness and the residue was purified by HPLC chromatography. H-Asp-Gly-Arg-His-Asp-Leu-OH was obtained, R 2 = 9.5, M 712.

Analogously, it is obtained by removing the protecting groups of the compounds of Example 1 as starting materials:

H-Gly-Arg-His-Asp-Leu-OH; RZ = 9.2; I '? 597;

H-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OK; RZ = 11.3; 883;

Π-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH; RZ = 12.9; M ⁺ 982;

H-Asp-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH; RZ = 13.4; P? 1097;

H-Lys-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Leu-OH; RZ = 11.5; 1011;

H-Tyr-Gly-Gly-Gly-Asp-Gly-4RG-His-Asp-Leu-0H; SS - 13.8; K ⁺ 1046;

H-Ala-Asp-Gly-Phe Arg-His-Asp-Leu-OH; RZ = 10.7; M ⁺ 783; HB-Ala-Asp-Gly-Arg-His-Asp-Leu-OH; RZ = 11.1; M ⁺ 783; H-Gly-Asp-Ala-Arg-His-Asp-Leu-OH; RZ = 11.0; I '.? 764; H-Gly-B-Asp-Gly-Arg-His-Asp-Leu-OH; SS - 10.5; 770;

H-Gly-Asp-B-Ala-Arg-His-Asp-Leu-OH; RZ = 11.9; M ⁺ 784;

H-Gly-Asp-Arg-His-Asp-Leu-OH; RZ = 8.1; M 712;

H-Cys (Trt) -Gly-Gly-Gly-Asp-Arg-His-Asp-Leu-OH; R 2 = 27.7 M ⁺ 1171;

H-Cys-Gly-Gly-Gly-Asp-Arg-His-Asp-Leu-OH; RZ = 11.7; M

929;

H-Cys (Trt) -Gly-Gly-Gly-Asp-Gl, γ-Arg-His-Asp-Leu-OH; RZ =

27; M ⁺ 1228;

H-Cys-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Leu-OH; RZ = 11.7; W ⁺ 987;

H-Cys-Gly-Gly-Thr-Asp-Asn-Vel-Gly-Asp-Gly-Arg-IIIs-Asp-Leu-OH; RZ = 12.7; 1415;

H-Thr-sp ^ Ves-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH.

Example 5

Analogously to Example 4, the saponification and cleavage of the BOC-protecting groups from the compounds of Example 2 are obtained as starting materials:

H-Gly-Asp-Gly-Phe Arg-His-Asp-OH; R 2 = 3.5; M ⁺ 656; H-Gly-Gly-nsp-Arg-His-OH; R 2 = 3.5; M ⁺ 541; K-Gly-Asp-Gly-Arg-His-Asn-Leu-OH; 11.2; M ⁺ 769; H-Gly-Asp-Gly-Arg-Gly-Asp-Leu-OH; RZ = 11.4; M ^4689; H-Gly-Asp-Gly-Arg-His-L-Asp-Leu-OH; RZ = 11.7; M ⁺ 769; H-Gly-Asp-Gly-Arg-D-His-Asp-Leu-ΟΠ; RZ = 11.3; M ⁺ 769;

H-Gly-Asp-Gly-l-Arg-His-Asp-Leu-OH; RZ = 10.9; M 769;

H-Gly-Asn-Gly-Arg-His-Asn-Le-of-OH; RZ = 10.8; M 767;

K-Gly-Asn-Gly-C-Arg-His-Asp-Leu-OH; RZ = 11.6; M 768.

Example 3

Analogously to Example 4, the compounds of Example 3 are obtained by granulating and cleaving the BOC-protecting groups:

H-Leu-Asp-His-Arg-Gly-Asp-Gly-OH; RZ = 11.1; M ⁺ 769;

H-Lys-Gly-Gly-Gly-Asp-Arg-Leu-His-Asp-Gly-OH; RZ = 9.8; l / 1011;

H-Lys-Pro-Ser-Asp-Gly-Arg-Gly-OH; R 2 = 3.5; M ⁴ 716; H-Arg-His-Asp- ^LJ eu-OH; RZ = 8.0; I, ⁺ 540;

H-D-Lys-D-Pro-D-Ser-D-Asp-D-Gly-D-Arg-Gly-Phe-OH; RZ = 24.7; 938;

H-Leu-Asp-His-Arg-Gly-Asp-OH; RZ = 11.5; M ⁺ 712;

K-Asp-Leu-His-Arg-Gly-OH; RZ = 3.9; M ⁺ 597;

H-Gly-Arg-His-Asp-Leu-Leu-OH; RZ = 15.3; M ⁺ 710;

H-Arg-Gly-Asp-Leu-OH; R 2 = 7.0; M ⁺ 460;

H-Cys-Gly-Gly-Gly-Asp-Arg-Leu-His-Gly-OH; RZ = 7.2; M ⁺

871;

H-Cys-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Ile-OH; RZ = 15.1;

I

⁺ 986.

Example 7

0.9 g of H-Arg-His-Asp-Leu-OH was dissolved in 200 ml of aqueous NH 3 and 0.5 g of acetyl chloride dissolved in 10 ml of dichloromethane was added dropwise with stirring and the mixture was stirred for 15 minutes. and vigorously evaporates. The precipitated product is separated. H-C-CO-Arg-His-Asp-Leu-OH is obtained, HZ = 12.4; M ⁺ 582.

Analogously, it is obtained by acetylation

II-Gly-Asp-Gly-Arg-His-OH:

H ^ C-CO-Gly-Asp-Gly-Arg-Kis-OH;

H-Arg-Gly-Asp-Leu-OH:

H ^ C-CO-Arg-Gly-Asp-Leu-OH; H 2 = 13.0; M ⁺ 502; '

H-Lys-Pro-Ser ^ al-Gly-Arg-Gly-OH:

HJC-CO-Lys-Pro-Ser-Asp-Gly-Phe Arg-Gly-OH;

H-Arg-His-Asp-Leu-OH:

To ties-CO-Arg-Kis-Asp-Leu-OH;

Η-Γ-Lys-D-Pro-D-Ser-D-Asp-D-Gly-L-Arg-D-Gly-OH:

HJC-CO-D-Lys-D-Pro-L-Ser-L-Asp-Gly-B-D-Arg-D-Gly-OH;

K-Asp-Leu-His-Arg-Gly-Asp-OH:

H ^ C-CO-Asp-Leu-His-Arg-Gly-Asp-OH;

H-Leu-Asp-His-Arg-Gly-OH:

H ^ C-CO-Asp-Leu-His-Arg-Gly-OH,

Example 6

Analogously to Example 1, it is obtained by condensing H 2 C-CO-Gly-Asp-Gly-Arg-His-OH with H-Asp-Leu-OMe and then saponifying H 2 C-CO-Gly-Asp-Gly-Arg- Ris-Asp-Leu-OH; RZ =

14.1; 811th

Example 9

2.0 g of BOC-Gly-Arg-Kis-Asp-Leu-OMe were stirred in 25 ml of dioxane-based 4N hydrochloric acid for two hours. The reaction mixture was then concentrated, the residue was dissolved in 100 ml of IMF and cooled to 0 ° C. The equivalent of Fmoc-Gly-Gly-Gly-Asp-OK, 1.3 g TBTU and 1.0 ml trietvlemine are then added sequentially. The solution was stirred at 0 ° C for 2 hours at room temperature for 12 hours. After re-concentration, the concentrate is poured into NaKCO3 solution. The precipitated product is filtered off, dissolved in 50 ml of methanol, treated with 1.5 ml of 2N NaOH solution, stirred for 4 hours at 25 DEG C. and worked up in the usual manner. There was obtained Fmoc-Glv-Gly-Glv-Asp-Gly-Arg-His-Asp-Leu-OH, R 2 = 28.0, J ⁺ , ⁺ = 1105.

Analogously with the condensation of H-Arg-His-Asp-Leu-OMe:

with Fmoc-Gly-OH:

Fmoc-Gly-Arg-His-Asp-Leu-OH, with Fmoc-Asn-Gly-Asp-Gly-OH:

Fmoc-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OII, with Fmoc-Vel-Asn-Gly-Asp-Glv-OII:

Fmoc-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, with Fmoc-Asp-Vgl-Asn-Gly-Asp-Gly-OH

Fmoc-Asp-in-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, with Fmoc-Lys-Gly-Gly-Gly-Asp-Gly-OH:

Fmoc-Lys-Gly-Gly-Gly-Asp-Glv-Arg-His-Asp-Leu-OH, with Fmoc-Tyr-Gly-Gly-C-ly-Asp-Gly-OH

Fmoc-Tyr-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, with Fmoc-Ala-Asp-Glv-OH:

Frnoc-Ala-Asp-Gly-Arg-His-Asp-Leu-OH, with Fmoc-1'-Ala-Asp-Gly-OH obtains:

Fmoc-D-Ala-Asp-Gly-Arg-His-Asp-Leu-OH with Frooc-Gly-Asp-OH ^rt ls obtained:

Fmoc-Gly-Asp-Ala-Arg-His-Asp-Leu-OH, with Fmoc-uly-1'-Asp-Gly-OH:

Fmoc-Gl-y-E-Asp-Gly-Arg-Kis-Asp-Leu-OH, with Fmoc-Gly-Asp-1'-Ala-OH obtains:

Pmoc-Gly-Asp-1-Ala-Arg-His-Asp-Leu-OH, with Fmoc-Gly-Asp-OH:

Fmoc-Gly-Asp-Arg-His-Asp-Leu-OH, with Fmoc-Cys (Trt) -Gly-Gly-Gly-Asp-OK

Fmoc-Cys (Trt) -Gly-Gly-Gly-Asp-Arg-Arg-Is-Asp-Leu-OH, with Fmoc-Cys-Gly-Gly-Gly-Asp-OH:

Pmoc-Cys-Gly-Gly-Gly-Gly-Asp-Arg-His-Asp-Leu-OH, with Fmoc-Cys (Trt) -Gly-Gly-Glv-Asp-Gly-OH

Fmoc-Cys (Trt) -Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Leu-OH with Fmoc-Cys-Gly-Gly-Gly-Asp-Gly-OH gives:

Fmoc-Cys-Gly-Gly-Gly-Asp-Gly-Arg-Eis-Asp-Leu-OH, with Fmoc-Cys-Gly-Gly-Thr-Asp-Val-Asn-Gly-Asp-Gly-OH Fmoc-Cys-Gly-Gly-Thr-Asp-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, Fmoc-Thr-Asp-Val-Asn-Gly-Asp-Gly- OH will get:

Finoc-Thr-Asp-Asn-Vsl-Gl y-Gly-Asp-Arg-His-Asp-Leu-OH.

Example 10

0.7 g of BOC-Gly-Asp-Gly-Arg (BOC) -His-Asp-Leu-OH was dissolved in 100 ml of dichloromethane, treated with 1.4 equivalents of MBHA resin and stirred at room temperature for 24 hours. After removal of the solvent, BOC-Gly-Asp-Gly-Arg (BOC) -1,11-Asp-Leu-1'BHA resin was obtained, which was taken up in 20 ml of 2N HCl based on dioxane and stirred at room temperature for 2 hours. rooms. Subsequent treatment with TFA provides the respective ^{H-Gly-Asp-Gly-Arg-His-Asp-ij} _eu-NH2, R = 8.8, R? ⁺ 768.

Analogously the following peptide amides are obtained by reaction with MBHA resin:

from B0C-Arg (B0C) -His-Asp-Leu-OH:

H-Arg-His-Asp-Leu-NH _2; RZ = 5.4; M ⁺ 539;

from BOC-Arg (BOC) -Gly-Asp-Leu-OH:

H-Arg-Gly-Asp-Leu-NH _2; RZ = 4.7; M ⁺ 459;

from I30C-Gly-Asp-Gly-Arg (BOC) -Gly-Asp-Leu-OH: H-Gly-Asp-Gly-Arg-Gly-Asp-Leu-NH ₂ .

j, Example 11 i

Analogously to Example 7, the peptide H-C-CO-Gly-Asp-Gly-Arg-His-Asp-Leu-NH ₂ is obtained from the starting H-Gly-Asp-Gly-Arg-His-Asp-Leu-NH _{2 by} acetylation. NH ₂ ; SS - 12.4; 810th

Analogously obtained;

- 31 of H-Arg-His-Asp-Leu-NH _^2:

H 2 C-CO-Arg-His-Asp-Leu-NH ₂ ; RZ = 11.1; M 581;

of H-Arg-Gly-Asp-Leu-NH _2:

H 2 CO-Arg-Gly-Asp-Leu-NH ₂ ; RZ = 11.3; M ⁺ 501.

Example 12 mg of H-Thr-Asp-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH was dissolved three to four times in 0.01 M HCl and freeze-dried after each dissolution. Subsequent HPLC purification provides H-Thr-Asp-Val-Asn-Glv-Asp-Gly-Arg-His-Asp-Leu-QH x HCl.

Analogously from H-Thr-Asp-Vel-Asn-Gly-Hsp-Gly-Arg-His-Asp-Leu-OH by treatment with TFA:

H-Zhr-Asp-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH x TFA, R 2 = 11.8, M ⁺ 1198.

Example 13

For the preparation of the affinity phases, 0.9 g of N-maleimido-CH 2 Q-CO-NH-C 1 H 4 -polymer (obtainable by condensation of N-maleimido-C 1 H 4 -Q-COOH with 1 N 2 R 3 H 3 -) is suspended. polymer) in 10 ml of 0.1 M sodium phosphate buffer at pH 7 and 1 equivalent of H-Cys-Gly-Gly-Gly-Asp-Arg-His-Asp-Leu-OH was added at 4 ° C. After stirring for 4 hours while warming the reaction mixture to room temperature, the solid residue is filtered off and washed twice with 10 ml of buffer solution (pH 7) and then washed three times with 10 ml of water each time. H-Cysyl 3- (N-nitinimido-C 1 H 2 -CO-NH-C 1 H 8-polymer) -Gly-Gly-Gly-Asp-Arg-His-Asp-Leu-OII was obtained.

Example 14

Analogous to Example 1, polymer-OCáciouHg-Nl · (commercially available) and HOOC-C ^HgCO-Gly-Asp-Gly-Arg-His-Asp-Leu-OMe (available by condensation of adipic acid) are obtained by condensation with HG.ly-Asp-Gly-Arg-His-Asp-Leu-OMe under the above conditions) this polymer phase:

polymer-O-C CHg-NH-CO-C ^Hg-CO-Gly-Asp-Gly-Arg-His-Asp-Leu -OMe. The polymer-O-C1-Hg-HH-CO-Gly-Asp-Glv-Arg-His-Asp-Leu-OH is obtained after saponification in methanol with 21M NaOH solution according to Example 4.

the following examples relate to pharmaceutical preparations:

Example A Vials

A solution of 100 g of an active compound of the formula I and 3 g of sodium hydrogen phosphate in 3 l of double-distilled water is adjusted to pH 6.5, sterile filtered, filled into vials, lyophilized under sterile conditions and sealed under sterile conditions. Each vial contains 5 mg of active substance.

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 of 1 g of an active compound of the formula I is prepared, 9.38 g NaH ₂ PO ₄ x 2 H ₂ O, 28.48 g Ka ₂ HP-J x HgO and 0.1 g benzalkonium chloride in 940 ml twice distilled water. The pH is adjusted to 6.8, made up to 1 L and sterilized by irradiation. This solution can be used in the form of eye drops.

Example P Part I

300 mg of an active compound of formula E are mixed with 99.5 g of petrolatum under aseptic conditions.

Example E Tablets

Mix ^! 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are compressed in a conventional manner into tablets, each containing 10 mg of active ingredient.

Example F Drsée

Analogously to Example E, tablets are compressed and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

EXAMPLE G Capsules i 2 kg of an active compound of the formula I are conventionally prepared in a conventional manner. filled into hard gelatin capsules, such that; each capsule contains 20 mg of the active ingredient.

Example H Ampoules j

A solution of 1 kg of the active compound of the formula I in 60 ml of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed. Each sypula contains 10 mg of the active ingredient.

Claims (9)

PATENT CLAIMS 1. Linear peptides of the general formula I X - A - B - C - Arg - E - G - L - Z (I) wherein is XH, C 1 -C 10 acyl, Η-Asn, H-Val-Asn, H-Asp-Val-Asn, Fmoc-Gly-Gly, II-Lys-Gly-Gly, H-Lys-Pro, H- Tyr-Gly-Gly, II-Cys-Gly-Gly, H-Cys (Trt) -Gly-Gly, H-Cys-Gly-Gly-Thr-Asp-Val-Asn or H-Thr-Asp-Val-Asn . A, B, and C independently of each other are absent or are each an amino acid residue selected from the group consisting of Ala, Arg, Asn, Asp, Asp (OR), Cys, Gln, Glu, Gly, His, Ile, Phe, 4-Kal -Phe, Pro, Ser, Thr, Trp, Tyr or Val, wherein said amino acid residues may also be derivatized, E is Gly, His or Leu-His, G is absent or is Asp or Asn, L is missing or means Gly, Ile, Leu or Leu-Leu, Z is NH ₂ θΐθ ^ ο OH, Bal means F, β _Γ I a Ac is a C 1 -C 10 alkanoyl, and physiologically acceptable salts thereof. I The enantiomer or dlastereomer of a compound of formula I according to claim 1. Third (a) H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, (b) Π-Thr-Asp-Val-Asn-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, (c) H-Lys-Gly-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, (d) Fmoc-Gly-Gly-Gly-Asp-Gly-Arg-His-Asp-Leu- OH, (e) CH 2 -CO-Gly-Asp-Gly-Arg-His-Asp-Leu-OH, (f) H-Cys-Gly-Gly-Asp-Arg-His-Asp-Leu-OH, ( g) H-Gly-Arg-His-Asp-Leu-OH. Processes for the preparation of compounds of formula I according to claim 1 or salts thereof, characterized in that the compounds are released from their functional derivative by treatment with a solvolyzing or hydrogenolyzing agent, or that the compound of formula II M-Z Z is as defined above and Ivi is (a) X, but not hydrogen, Emoc-Gly, H-Lys-Gly, H-Lys, H-Tyr-Gly, H-Asp-Val, II-Tyr, H-Val, II-Asp, H -Cys-Gly-Gly-Thr-Asp-Val, H-Cys-Gly-Gly-Thr-Asp, H-Cys-Glv-Gly-Thr -Cys, H-Cys (Trt) -Gly, H-Cys (Trt), H-Thr-Asp-Val, H-Thr-Asp, or H-Thr, (b) XA, (C) X-A-B-C-Arg-E, or (g) X-A-B-C-Arg-E-G is reacted with an amino compound of Formula III H-Q-Z (III) wherein Z is as defined above and Q stands for (a) HABC-Arg-EGL, H-Gly-ABC-Arg-EGL, H-Val-Asn-ABC-Arg-EGL, H-Gly-ABC-Arg-EGL H-Gly-Gly-ABC-Arg-EGL, II-Asn-ABC-Arg-EGL, H-Asp-Val-Asn-ABC-Arg-EGL, H -Thr-Asp-Val-Asn-ABC-Arg-EGL-H-Gly-Thr-Asp-Val-Asn-ABC-Arg-EGL or H-Gly-Glv-Thr-Asp-Val-Asn-ABC-Arg -EGL, (b) PBC-Arg-EC-L, (c) HC-Arg-EGL, (d) H-Arg-EGL, (e) KEGL, (f) HGL, or (g) HL, and / or optionally, the free amino acid is sylated with / or the compound of formula I is treated with an acid or base and converted to its salt, A process for the manufacture of pharmaceutical preparations, characterized in that the compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-solid carrier or excipient. . A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 or a physiologically acceptable salt thereof. The use of the compounds of formula I according to claim 1 or their physiologically acceptable salts for the manufacture of a medicament for controlling diseases. Use of the compounds of claim 1 or of their physiologically acceptable salts in the control of diseases. Use of compounds of formula I according to claim 1 for the production of immobilized ligands for affinity column chromatography. 10.. Use of compounds of the formula [according to claim 1] for purification of integrins by random chromatography.