Rgd-like peptides

FIELD: chemistry.

SUBSTANCE: invention discloses novel synthetic RGD-like peptides capable of dose-dependant inhibition of thrombocyte aggregation.

EFFECT: obtaining novel compounds capable of dose-dependant inhibition of thrombocyte aggregation.

2 tbl, 1 ex


The invention relates to medicine, in particular to the synthesis of pharmacologically active compounds.

The problem of prevention and treatment of thromboembolic complications continues to be relevant for modern medicine. In the last decade was established the key role of platelets in the development of cardiovascular diseases. Figuring out such important values of platelets stimulated the development of a large number of drugs. Antiplatelet tools have long been an integral part of the treatment of patients with myocardial infarction (mi), heart failure, coronary heart disease (CHD).

The prevention and treatment of these diseases remain relevant, as they remain the leading cause of death in both male and female population in developed and developing countries. These questions are of paramount importance for national health care, because unlike the US and most European States, Russia failed to reduce the incidence of coronary heart disease, over the past two decades. For each doctor has long been axiomatic that the key to solving this problem is to combat risk factors for the disease, among which the focus is atherothrombosis.

Aerodromes - thrombus formation on n the surface damaged atherosclerotic plaques, is the main pathogenetic mechanism of its growth and development of complications of atherosclerosis. Thrombotic complications of atherosclerosis, especially myocardial infarction (mi) and stroke occupy a leading place in the structure of total mortality in most developed countries. In Russia the situation is particularly bad: the share of cardiovascular diseases account for the majority of deaths - 55,4%, while atherothrombosis is the cause of death in 30% of cases.

Antithrombotic therapy is recognized as the basis of the pathogenetic treatment of both acute and chronic forms of coronary heart disease. The main directions of antithrombotic therapy are: inhibition of platelet function, the impact on the system gemokoagulyatsii, restoration of patency of the vessel when it is thrombotic occlusion (thrombolysis).

Given the prevalence and the progressive increase of the pathologies of the circulatory system in the world, as well as a relatively high percentage of mortality of patients, the development of fundamentally new antithrombotic drugs is a particularly pressing issue.

The greatest attention of experts recently brought to antiplatelet agents that block the aggregation of platelets and erythrocytes. To antiplatelet agents are the drugs of different mechanisms of action and belong to separate the groups of chemical compounds.

Peptides belonging to the class of RGD (Arg-Gly-Asp)-stimulants are powerful inhibitors of platelet aggregation. Antiplatelet effect of RGD-peptides due to their ability to prevent the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to glycoprotein llb/llla receptor of platelets.

In US patent No. 5,292,756; Granted: March 8, 1994 was screened natural proteins with antiplatelet activity derived synthetic peptides similar actions carried out their identification and analysis. Developed injectable dosage form of the synthetic peptides antitromboticescoe actions.

However, analyzing the data, it should be noted that the resulting dosage forms do not possess satisfactory stability, possibly due to the presence of impurities inevitably present in the preparations obtained in laboratory synthesis.

In the patent RU 2119354, AK 47/48, 1998 describes a directed transport of drugs, which is binding in vivo carrier molecules pharmacological compounds with uniform elements of blood involved in the pathological process. To link the original synthesized derivatives of pharmacological agents and peptide containing RGD (carboxymethyl-5-fluorouracil-atsetamidometil-cysteinyl-arginyl-glycyl-aspart is l-atsetamidometil-cysteine and acetylsalicylic-aspartyl-S-nitronicotinic).

It should be noted that in the above patent, the amino acid composition of the peptide differs from the proposed and is not considered antithrombine action. The synthesized peptide is used only as a carrier of pharmacological compounds to places increased adhesion of platelets.

Heterodimer GPIIb/IIIa (also known as integrin αIIb3) is a surface receptor of platelets. In the process of CA2+-dependent activation of the complex undergoes a series of conformational changes that allow binding with platelet fibrinogen.

Functioning IIb/IIIa-receptor is its ability to learn two characteristic amino acid sequence. The first consists of the amino acids Arg-Gly-Asp, it is found in fibronectin, von Willebrand factor, vitronectin, and also in the α-chains of fibrinogen molecules, and for each half of fibrinogen molecule has two key sequence Arg-Gly-Asp. It should be emphasized that the "key" sequence Arg-Gly-Asp recognized by most members of the family of integrins. Detailed mechanisms of interaction IIb/IIIA receptor with adhesive molecules is not fully understood, but it is obvious that the peptides or small molecules that contains the key amino acid sequence Arg-Gly-Asp may be sweat the social inhibitors interaction IIb/IIIa receptors on platelets with fibrinogen.

GPIIb consists of located on the surface of the platelet heavy chain with a mass of 116 KD, covalently linked by one disulfide bond with the light (22 KD) chain, which is a transmembrane protein. GPIIIa-subunit is glycosylated polypeptide with a mass of 90 KD, which consists of three domains, a large extracellular region at N-end, a transmembrane domain and a short cytoplasmic segment at the C-end.

Blockers IIb/IIIa receptors of platelets are the youngest group of the whole class, antitromboticeskih drugs used in cardiology. The mechanism of operation of this group consists in inhibition of total final phase of platelet aggregation - build process of a blood clot by forming bridges between adjacent activated platelets from molecules of fibrinogen. Activation of platelets by different agents (ADP, thrombin, thromboxane A2, collagen) leads to shape changes (activation) of platelets and activation of GP IIb/IIIa. As a result of platelet activating configuration IIb/IIIa receptor changes, which increases their ability to commit fibrinogen and other adhesive proteins. The binding molecules of fibrinogen with IIb/IIIa receptors on different platelets leads to the connection of the plates with each other - aggregation. This process does not depend on the type of activator and is the end is the first and only mechanism of platelet aggregation. Inhibitors of receptor GPIIb/IIIa is also associated with GPIIb/IIIa, blocking the binding of fibrinogen, and thus prevent the aggregation of platelets.

Task is the creation of new peptides.

The problem is solved peptides:


Arg-Aminovaleric acid-Asp-Trp




Based on previously obtained data [Pollina E. Design and sinthesis of RGD mimetics as potent inhibitors of platelet aggregation // J. Undergrad. Sci. - 1996. - 3: 119-126; I. Ojima, S. Chakravarty, Dong Q. Antithrombotic agents: from RGD to peptide mimetics // Bioorganic & Medicinal Chemistry. - 1995. - Vol.4. - P. 337-360; Melnyk, O., Martinovich VP, Golubovich VP Communication patterns and antiaggregatory activity in a series of analogues Arg-Gly-Asp // Bioorganic chemistry. 2006, vol 32, No. 2, str-143], we can assume that as a staging area, it is preferable to use β-alanine, valeric acid, or a combination of glycine-glycine. Such fragments of the molecule will allow to obtain the desired conformation and increase the biological activity of the peptide molecules. As the hydrophobic site, you should probably use tryptophan. For substances with such a hydrophobic group obtained the best results [Pollina E. Design and sinthesis of RGD mimetics as potent inhibitors of platelet aggregation // J. Undergrad. Sci. - 1996. - 3: 119-126]. The areas represented by the arginine and aspartic acid, it makes sense to leave unchanged.

Synthesis of peptides b is l performed on solid phase using a peptide synthesizer, Applied Biosystems 433A, using the Fmoc-strategy. It is based on the sequential joining of amino acid residues to an insoluble polymeric substrate. The base labile Fmoc group is used to protect the N-group of each amino acid residue. Those residues that are potentially reactive side chain-protected kislotoneustoichiwami groups, type tertbutyl.

After removal of the Fmoc group with piperidine, the following protected amino acid is added, or using a coupling reagent or pre-activated derivative of the amino acid.

As the activator of the first amino acid Fmoc-strategy in response attach it to the resin is dicyclohexylcarbodiimide

As the activator of the first amino acid Fmoc-strategy in response attach it to the resin is dicyclohexylcarbodiimide (DCC). The reaction proceeds in the presence of 4-dimethylaminopyridine (DCC/DMAP), which plays the role of catalyst. The result is an activated amino acid.

As the activator of the second and subsequent amino acid Fmoc-strategy is 1-hydroxybenzotriazole in dicyclohexylcarbodiimide (HOBt/DCC). The reaction proceeds in accordance with the formation of the activated amino acid and N,N'-dicyclohexylmethane (DCU).

All of the above operations take place in a peptide synthesizer.

To remove pept is Yes with resin in a fume hood in a polypropylene test tube was prepared mixture with the following ratio of components: TAN 2.5 PERCENT, TIPS AND 2.5%EDT / - 5%, TFA - 90%. The mixture was placed on ice to cool for 20-30 minutes Then cool the mixture to remove the peptide was placed in the peptide-resin and gently stirred. Put the tube with the peptide-resin in the polypropylene tube was closed and kept on shaker for 4 hours.

Extraction of the peptide from the resin was carried out on a glass filter funnel in a fume hood. Funnel previously opolaskivatel double-MTBE (methyl tertiary butyl ether). After removing poured the mixture with the resin and the peptide on the filter SCHOTT. Washed test tube, which was the reaction of TFA, wash was poured into the filter. Filtered at low vacuum to the dry resin. Added cold MTBE, thoroughly washed resin and filtered before drying. Washed test tube that contained the peptide-resin three times with cold MTBE and added flush to the main drain. Thoroughly mixed suspension. Leave the mixture for about 2 minutes. Then selected 100 (l of the resulting solution for analysis. (Storage temperature 4°C until analysis). The remaining mixture was left for at least 1 hour at -20°C. the mixture was Centrifuged at 1500 g for 6 min, separated supernatant. To the precipitate was added MTBE, rubbed with a spatula and freeze for 2 hours. The operation of the freezing - thawing was repeated twice.

Freeze-drying of the peptide was carried out and the 0.01 M phosphate-saline buffer after dilution obtained after extraction of sediment.

Purification was performed by high performance liquid chromatography (HPLC).

Conditions for HPLC: column Waters DeltaPak, C18, 5 μm, 100 Å, a 3.9×150 mm Can be used other obrasheniyashi column C18 or C8.

A. The detector cell: analytical

b. Flow rate - 1.0 ml/min

C. wavelength: 214 nm

d. Detection range: 0,5 AUFS

that is, the value of the loop: 100 μm (the loop is filled with 150 [±10] ml sample, that is, the injection amount = 100 ml)

f. Eluent A: 5.0% acetonitrile, 0.1% triperoxonane acid in water.

g. Eluent B: 60% acetonitrile, 0.085% triperoxonane acid in water.

h. Gradient: 0-60% b for 60 minutes

To confirm the structures of these peptides were used nuclear magnetic resonance (NMR). Conducted a one-dimensional NMR spectroscopy for protons (1N) and carbon (13C). To conduct1H and13With the NMR sample of the peptide was dissolved in DMSO-d6 with isotopic purity of 99.9% D. an NMR Spectrum1N received spectrometer "Evans-300" with a resonance frequency of 300 MHz. Concentration measurement of the proton chemical shifts were performed at a temperature of 296.6 K. All NMR measurements were performed under conditions of fast exchange of the interacting molecules in the time scale of NMR. The chemical shift was determined relative to the internal standard tetramethylsilane (TMS). The obtained pattern of chemical shifts and intensivstation confirm the composition of substances.

The assessment of specific activity antiaggregatory action of the peptides was performed in vitro using blood of healthy donors and patients with giperagregatsiyu platelets. The blood sampling was performed immediately before the study, using as an anticoagulant sodium citrate (3.8 percent). The ratio of anticoagulant: blood corresponds to 1:9. Antiaggregatory activity of the obtained compounds was studied in platelet-rich plasma using ADP as an inducer of platelet aggregation.

To prepare platelet-rich plasma blood immediately after receiving centrifuged for 10 minutes at 1000 rpm, after which the top plasma layer was transferred to another tube, and the remainder was centrifuged for 20 minutes At 3000 rpm to obtain estramboticos plasma. All procedures were performed in polyster ware with thromboresistant properties. During the entire study period rich and estrambotica plasma was kept at room temperature, and the recording of platelet aggregation was carried out at 37°C.

To research specific antiaggregatory activity of the peptide was guided by the requirements for preclinical studies of pharmacological substances of this class approved Pharmacological service for supervision in the sphere of healthcare is social development.

The study aggregation was carried out according to the method G.G.V.Bom. The study was performed on the device LA230-2 ("Biola", Russia). The volume of the cell is 200 ál. As the inductor used ADP in a concentration of 10-7M. the platelet Count was recorded by the device. The peptide was studied at a concentration of 10-3, 10-4, 10-5, 10-6M was added immediately before the addition of ADP. As a standard solution was used "Eptifibatide" in the same concentrations. The results are presented in table 2.

In the study of inhibitory effect on platelet aggregation in healthy donors was detected in a dose-dependent effect of inhibition of platelet aggregation for all six compounds, but the most active inhibitor was Pentapeptide Arg-Gly-Gly-Asp-Three connection inhibited ADP - induced platelet aggregation with IC506.3 µm (table 1).

When studying the effect of the peptide on the platelets of patients with giperagregatsiyu was detected occurrence of phase disaggregation, which is absent in the control group, indicating a continuous aggregation action of ATP. Thus, it was found inhibition of aggregation induced by peptide both groups of blood, which shows a marked antiaggregatory effect.

Table. 1
The effect of RGD-peptides on the inhibition of ADP-induced platelet aggregation in vitro
ConnectionIC50microns (ADP, 1.5 mm)
Arg-Aminovaleric acid-Asp-Trp19,8

Table. 2
Study of specific antiaggregatory activity of the peptide Arg-Gly-Gly-Asp-Trp
The concentration of peptidePlatelet aggregation
The peptide Arg-Gly-Gly-Asp-TrpStandard Eptifibadide"
% of control% inhibition% of control% inhibition
10-6M 69,8±5,030,2±2,587,4±6,912,6±1,1

RGD-peptides selected from the group:
Arg-Aminovaleric acid-Asp-Trp,


Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology and is a peptide which induces killer T cells ex vivo and which has an amino acid sequence as shown in one SEQ ID NOS: from 1 to 3. The disclosed peptide is used in an ex vivo agent for inducing anti-tumour immunity, in an ex vivo agent for inducing antigen-presenting cells, in an ex vivo agent which induces tumour-reactive T cells, as well as in an ex vivo pharmaceutical agent when treating or preventing tumours. The invention also relates to an antibody against the said peptide.

EFFECT: disclosed agents enable identification of glypican-3-derivative peptide, which can bond with HLA-A2, and activation of human killer T cells in order to provide an immunotherapy agent which may be effective in approximately 40% Japanese patients suffering from certain types of malignant tumours, accompanied by high level of GPC3 expression.

7 cl, 4 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to contrast agents which contain a peptide vector linked with uPAR, marked with a visualising group.

EFFECT: obtaining a contrast agent for detecting urokinase plasminogen activator receptor.

6 cl, 6 ex

Peptide compounds // 2393167

FIELD: chemistry.

SUBSTANCE: invention relates to novel peptide compounds and their use in diagnostic optical visualisation techniques. More specifically, the present invention pertains to use of such peptide compounds as targeted vectors which are related to receptors associated with angiogenesis. The compounds are labelled using at least one cyanine reporter dye.

EFFECT: obtaining compounds which can be used as contrast agents in optical visualisation when diagnosing diseases related to angiogenesis.

9 cl, 5 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth factor activity towards fibroblast proliferation and can be used in medicine. An oligopeptide of formula A-X1-X2-X3-X4-X5-B is obtained through in silico construction, where A is F; X1 is E, or Q, or S; X2 is N, or Q, or A, or G; X3 is K, or R, or T; X4 is K, or E, or is absent, X5 is K, or L, or is absent and B is OMe - methyl.

EFFECT: invention enables obtaining an oligopeptide with transformation growth factor (TGF-β) and oncostatin M (OSM) towards fibroblast proliferation, and expansion of the range of effective therapeutic agents with wound-healing effect, which take part in closing wounds during inflammation and cicatrisation.

4 dwg, 2 ex

FIELD: chemistry; biochemistry.

SUBSTANCE: invention relates to bioengineering and specifically to obtaining biologically active substances of peptide nature, which have growth factor activity towards collagen synthesis stimulation and can be used in medicine. An oligopeptide of general formula A-X1-X2-X3-X4-X5-B (I) is obtained through in silico construction, where A is Ac - acetyl; X1 is G or A or is absent; X2 is P or I, or L, or V, or A; X3 is G; X4 is P or I, or L, or V, or A; X5 is G or A, or is absent and B is OMe - methyl.

EFFECT: invention enables obtaining an oligopeptide with acidic (aFGF) and transformation (TGF-β) growth factor activity towards stimulation of collagen biosynthesis, and expansion of the range of effective therapeutic agents with wound-healing effect, which speed up regeneration of damaged tissue and cicatrisation.

4 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: invention is related medicine and concerns applications of antibodies specifically recognising any prevailing variants of beta-amyloid peptide, Aβ40 and Aβ42, in preparation of a drug applied for prevention and-or treatment of Alzheimer's disease.

EFFECT: invention provides prevention of progression or reduction of symptoms, and/or decrease in amyloid deposition in an individual when administering an immunostimulating dose of peptide or specific antibody.

7 cl, 3 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: small peptides of formula X1-X2-X3-X4-X5-X6-X7-R1, containing 7-12 amino acid residues are proposed.

EFFECT: said peptides are MC4 receptor agonists and are therefore useful in treating obesity and related diseases.

31 cl, 2 tbl, 82 ex

FIELD: medicine.

SUBSTANCE: present invention concerns a compound representing a selective agonist of a melanocortin-4 receptor of formula: Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:50) and its pharmaceutically acceptable salts, pharmaceutical compositions and methods for application thereof in preparation of drugs.

EFFECT: higher effectiveness of compound application.

20 cl, 8 dwg, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to low-molecular derivatives of peptides which are used for preparing a pharmaceutical agent which inhibits laminin/nidogen reaction.

EFFECT: increased effectiveness of compounds.

2 cl, 12 dwg, 2 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention concerns preparation of peptide biologically active substances with activity of vascular endothelium growth factor (VEGF) with respect to angiogenesis stimulation, and can be used in medicine. In silico design is used for making oligopeptide of general formula I: A-X1-X2-X3-X4-X5-B (I) where A is Ac; X1 represents K or R; X2 represents either Q, or E, or N or D; X3 represents R or K; X4 represents either T, or F, or S, or L, or is absent, X5 represents To, or R, or is absent, and B represents OMe.

EFFECT: preparation of oligopeptides with VEGF activity, and extension of range of effective therapeutic agents that accelerates neogenesis.

4 dwg, 2 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention relates to derivatives of 2-hydroxytetrahydrofurane , of general formula (I) , which possess ability to inhibit calpaines and/or ability to catch active oxygen forms and can be used to obtain medication, intended for inhibiting calpaines and/or lipid peroxidation.

EFFECT: medications possess higher efficiency.

9 cl, 64 ex

FIELD: medicine.

SUBSTANCE: invention can be used for medical treatment of secondary hypothyroid state accompanied by low synthesis of thyrotrophic hormone by hypophysis and of iodine hormone by thyroid gland. Substance of invention implies application of peptide Lys-Glu-Asp-Gly as a medicine stimulating synthesis of thyrotrophic hormone by hypophysis and of thyroid hormone by thyroid gland.

EFFECT: high specific activity of introduced peptide and decrease of side effect risk.

4 tbl, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: releasing peptides of growth hormone are described with formula (I): R112345-R2, where:А1 designates Aib, Apc or Inp; А2 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl) or D-Тrp; А3 designates D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-2Ser(Bzl) or D-Trp; А4 designates 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); А5 designates Apc, Dab, Dap, Lys, Orn or deleted; R1 designates hydrogen; and R2 designates NH2; and their pharmaceutically acceptable salts.

EFFECT: pharmaceutical compositions and the methods of their application are presented.

25 cl, 1 tbl, 2 ex

The invention relates to new compounds of General formula I

R1-A-B-D-En-R2 (I)

in which R1 represents R12C(O), and R12 is selected from the group consisting of alkenyl, alkenylacyl or alkenylamine; And is a group A1-A2-A3, where A1 represents NH, A2 is a CHR93 in which R93 is 4-amidinophenoxy; A3 represents C(O); is a group B1-B2-B3, where B1 represents NH; B2 is a CHR97 where R97 represents ethyl, which is substituted in position 2 by hydroxycarbonyl or allyloxycarbonyl; B3 represents C(O); D represents a group D1-D2-D3, where D1 represents NH, D2 represents CR81R82 where R81 and R82 are independently selected from the group consisting of hydrogen and unsubstituted or substituted residues of alkyl, aryl, arylalkyl, heteroallyl; D3 represents C(O); Enis a (E1-E2-E3)nin which n is 0 or 1; E1 represents NR70, where R70 is H; E2 represents CR71R72, where R71 and R72 include independently selected from the group consisting of hydrogen and unsubstituted or substituted residues of alkyl, aryl, arylalkyl, heteroallyl; E3 represents C(O); R2 is a NR21R22 where R21 of iillil and geterotsiklicheskikh, moreover, the alkyl contains from 1 to 13 carbon atoms, alkenyl contains from 2 to 13 carbon atoms, aryl and heteroaryl contain from 5 to 13 ring carbon atoms, where in the rest of heteroaryl one or more carbon atoms are replaced by heteroatoms selected from the group consisting of N, O and S; heteroseksualci contains from 3 to 8 ring carbon atoms, of which from one to three carbon atoms are replaced by heteroatoms selected from the group consisting of N, O and S; in any stereoisomeric forms or their mixtures in any ratio, and their pharmaceutically acceptable salts; the method of obtaining compounds of General formula I, including linking protected amino acids; to pharmaceutical compositions which are able to exert an antithrombotic effect by activated factor VII(FVIIa) blood coagulation

The invention relates to oligopeptides derivative containing amino acid D-2-alkyltrimethyl, which is capable of releasing growth hormone (GH) from the somatotropic cells and active when administered orally

The invention relates to biotechnology and can be used for Introduzione nucleic acids into cells

The invention relates to Bioorganic chemistry, namely the synthesis of peptides possessing anxiolytic activity (the ability to control an alarm condition)

Caspase inhibitors // 2274642

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds that represent inhibitors of caspases, in particular, inhibitors of interleukin-1β-converting enzyme and their pharmaceutical compositions. Proposed compounds can be used successfully as agents directed against diseases mediated by interleukin-1, apoptosis and factor inducing interferon-γ or by interferon-γ.

EFFECT: valuable medicinal and biochemical inhibitors.

35 cl

The invention relates to new compounds which are inhibitors of interleukin-1-converting enzyme (IAP), is characterized by a specific structural formula; to pharmaceutical compositions having the ability to inhibit interleukin-1-converting enzymes, method of treatment and prophylaxis of diseases selected from the group consisting of IL-1-mediated autoimmune inflammatory, neurodegenerative diseases, as well as the selection method of the IAP inhibitor

The invention relates to new compounds of General formula I

< / BR>
where a is Gly; the remainder of the formula II

< / BR>
m= 0 or 1; n= 2 or 3; R1and R2each independently of the other represents H, R1and R2both together represent also

< / BR>

< / BR>
where IS -(CO)-(CH2)q-(CO)rwhere q=1, 2, or 3, r=0 or 1, or-CO-CH=CH-CO-; X IS H, Cl or1-C6alkyl; and if the mean remains optically active amino acids and derivatives of amino acids, are included as D-and L-forms, and their salts, process for the preparation of compounds of formula I and their salts; pharmaceutical composition having the ability to inhibit integrin containing in its structure at least one compound of the formula I and/or one of its physiologically acceptable salts