Lhrh antagonist decapeptides, pharmaceutical compositions comprising thereof and processes for their preparation

Description

Soluble LHRH*agonists, process for their preparation, and pharmaceutical compositions containing them The invention relates to LHRH antagonists with improved solubility, processes for the preparation of these compounds, medicaments containing these compounds, and the use of the medicaments for the treatment of hormone-dependent tumors and hormone-influenced, non-malignant diseases, such as benign prostatic hypertrophy (BPH) and endometriosis. The IUPAC-IB-Bizoftság Biochemical Nomenclature (European J. Biochem., 138: 9-37 (1984)) is used for naming peptides, according to which, in accordance with the usual representation, the amino groups are at the N-terminus, on the left, and the carboxyl groups are at the C-terminus, on the right. The peptide LHRH antagonists of the invention contain naturally occurring and synthetic amino acids, the most important of which are Ala, Val, Leu, He, Ser, Thr, Lys, Arg, Asp, Asn, Glu, Gln, Cys, Met, Phe, Tyr, Pro, Trp and His. The abbreviations of the individual amino acid residues are derived from the trivial names of the amino acids, such as Ala-alanine, Gly-glycine, leu-leucine, LysMIsine, Pal(3)3-(3-pyridinH)-alanine, Nal(2}~ S-^-naphthylj-alanine, Pbe-phenyl-alanine, Cpa~4-chlorophenyl~alanine, Pro-proline, Ser-serine, ?hr~threonine, Trp~tryptophan, 7yr~tyrosine and Sarosarkosine. All amino acids listed herein, unless otherwise indicated, belong to the L-series, for example 0-Nal(2) a 3-(2-naphthyl)- is an abbreviation for D-alan and Ser is for L-serine.Substitution at the s-amino group of the lysine chain is indicated by a notation in parentheses after Lys, optionally in the form of an abbreviation. Other abbreviations used: Atz 3-amino-1,2:4-triazolyl-S-carbene B 4-(4-amidino-phenyl)-amino-1,4-dioxo-butH Boa tertiary-butyl-oxy-carbonyl Bop Benzo triazoF 1 ~ox:í~tr lsz( d 1 methyl-amino )~phospho n ium-hexafl uo rphosphate DCC dicyclohexylcarbodiimide DCM dichloromethane Ddz dimethoxy-phenyl-(dimethyl-methylene-oxy)-xrbonyl (dI methoχí-dimethyl I ~Z) QIC Dilisopropylcarbodilimide P EÁ N, M~d iliisopropylethylamine ÖMF dimethylformamide Fmoc is fluoroenylmethyloxycarbonyl HF hydrofluoric acid (hydrogen fluoride) HOBt 1-hydroxybenzotriazole HPLC high-performance liquid chromatography: Me methyl TFA trifluoroacetic acid Z benzyloxycarbonyl The peptides of the invention are analogous to luteinizing hormone-releasing hormone (LHRH) and have the following structure: p-GIU“HiS“Trp“Ser-Tyr-GÍy~Leu-Arg-Pro-Gly-NH2, [LHRH, gonadorehnl. For more than 20 years, research has been conducted on selective antagonists of LHRH (decapeptidylcholine) [M. Karten et al., E. Rivière, Endocrine Reviews, 7: 44-66 (1986)]. These antagonists have attracted considerable interest in endocrinology, -due to their usefulness in the field of prevention and cancer treatment. A large number of compounds have been prepared as potential LHRH antagonists. The most interesting compounds found so far are those whose structures are modified versions of the LHRH structure. The first series of potent antagonists were obtained by introducing aromatic amino acid residues at positions 1, 2, 3 and 8 or 2, 3 and 6. The usual notation of the compounds is as follows: first, the amino acid that replaces the original amino acid in the peptide chain of LHRH is given, and then the position of the substitution is indicated by a superscript number. Furthermore, the term "LHRH" is used to indicate that the compound is an LHRH analog, in which the substitution [Ac-D-Cpa5,2, D~Trp3'e]LHRH is substituted in the LHRH molecule. H. Coy et al., in: Gross, E. and Melenhofer, J. (eds.) "Peptides; Proceedings of the SthAmerican Peptide Symposium", 775-779.oíd,sPierce Chem. Co., Rockville (1979)1; [Ac-Prot D-Cpa2, D-Nal(2)a,&jLHRH (U.S. Patent No. 4,419,347) and (Ac-ProT D~Cpa2, D-Trp'í's]LHRH [3. L.Píneda et al. J. Clin. Endocrinol Metab., 56: 420 (1933)]. To enhance the effect of antagonists, basic amino acids such as D-Arg were later introduced at position 6. For example, [Ac-D-Opa*·2, D-TrpA D-ArgT DÁla10JLHRH (GRG-3Ö276) (D. H, Coy et al., Endocnnology, 100:1445 (1982)1; and [Ao-D~Ral(2)', D-Phe(4~F)t D-Trp3, D-Arg®]LHRH (ORF 18260) (J, E. Rivíer et al., in: Vickery RH, Nestor, JrJJ., Hafez, ESE (eds.) "LHRH and its analogs", 11-22 pp,, MTP Press, Lankaster, UK., 1984}. Further potential LHRH antagonists are described in WO 92 / 19651, WO 94 / 19370, WO 92 / 17025, WO 94 / 14841, WO 94 / 13313, US-A 5,300,492, US~A 5,140,009, EP 0 413 209 A1 and DE 195 44 212 Al. The most recently described compounds contain a modified ornithine or lysine building block at position 8 and have the following general formula: Ac-D-INal(2)1-D~Cpa2-D«Pal{3}3-Ser4-Tyrs-D~Xxxe-Leu7-Arg8~Pro8-D~Alaw-NH2ía where D-Xxx is an amino acid group of general formula (VI). Other known LHRH antagonists include Antarelix, Ganirelix and Cetrorelix. Antarex: Ac-D~Nal(2)'~D-Cpa£~D~Pal(3)3'Ser4-Tyr5-D-Hci6-Leu7-Lys(íPr)s-Pros~D-Ala10 Ganirelix: NH Ao~D~Nal(2)t~D-Cpa2D-Pal(3)3-Ser4-Tyrs-D-hArg(Et)ALeu?~hArg(Et)2S-Pro9-D~ Ala'i0~HH2. Cetrorelix: Ac-D-Nal(2)1~D-Cpa2-D-Pa1(3)3-Ser4~Tyr5~D~Cífe-Leo7~Arg8-Pros~D-Alaw-NH2. The aim of the invention is to produce novel LHRH antagonists which have greater enzymatic stability and significantly improved water solubility. This purpose is served by Α-Χχχ'~Χχχ2-Χχχ3-Χχχ4~Χχχδ~Χχχδ~Χχχ7-Χχχδ~Χχχ9~Χχχ1δ~ΝΗ2 of general formula (I) - where A means acetyl- or 3-(4-0οοΓ-Ιοηϋ)~ρΓορίοηΙΙ~οδοροΗ; Xxx; means D-Nal(1} or D-Nal(2); Xxx2~Xxxs means D-Cpa~D~Pal(3) or a single bond; Xxx4 means Ser; Xx:xJ means N-Me-Tyr Xxx® D~Hci Xxxz means Nle; Xxx8 means Arg or Xxx9 means Pro; and Xxx10 means Ala or - compounds, and their pharmaceutically acceptable salts, especially acetates, embonates and trifluoroacetates. Further particularly preferred compounds of the invention are: Ac-D-Nal(2')-D-Cpa£-Ö-Pal(3)3-Ser4-N-Me-Tyr5DHcie“Nle7»ArgS“Pro8-DAla-O-NH2: Pc-D~Nal(2)'-ö--Cpa2-D-Pal(3)-Ser4-N“Me-Tyrs~D-Hde~Nle7-Lys(iPr)s~Pro8Sarw-NH2, AC'D-Nal(2)1-D-Cpaa-D-Pal(3)3“Ser4-N-Me~Tyr5-D-Hci&-Nle7~Arg8-Pro9~Sar1ö~ and salts thereof with pharmaceutically acceptable acids, The compounds of the invention can be used for the treatment of hormone-dependent tumors, especially prostate carcinoma or breast cancer, and for non-malignant diseases, the treatment of which requires LHRH suppression. For this purpose, the compound is mixed with the usual carriers and excipients and formulated as a pharmaceutical preparation. The compound of general formula (!) can be prepared by classical fragment condensation, or by Merhfeld's solid-phase synthesis, where in the successive steps of building the peptide, D-lysine is used, which is already acylated with a carboxylic acid of general formula R^-COOH on the side chain, or the decapeptide On the D-lysine6oS scaffold, an amide bond is formed with the appropriate carboxylic acid. Accordingly, the R^CO group can be introduced at three different points in the process: before the condensation of individual building blocks into the peptide; after the incorporation of lysine or ornithine into the peptide chain but before the introduction of subsequent building blocks; or after the condensation of all building blocks. The compound of general formula (I) is prepared in known ways, for example completely by solid-phase synthesis, by partial solid-phase synthesis techniques (so-called fragment condensation) or by classical coupling in solution. ffVL Bodanszky, "Principles of peptide synthesis, Springer Solid phase synthesis methods are described, for example, by JM Stewart and XÖ.Young (“Solid phase peptide syntheses”, Piarcé Chem. Company, Rockford, Ill. 1984), and by G. Bárány and RB Merriide (“The peptides”, Chapter 1, pp. 1-285, Academic Press inc., 1979). Classical solution synthesis is described in the manual “Methoden der Grganischen Chemíe (Houben-Weyl), Synthese von Pepiiden”, (ed.: E. VVünsch, 1974, Georg Thieme Verlag, Stuttgart, NSzK). The stepwise construction is carried out, for example, by first coupling the carboxyl-terminal amino acid, the amino group of which in the o-position is protected, to a conventional, insoluble support by a covalent bond, the protecting group of the o-amino group of the amino acid is cleaved off, then the next protected amino acid is coupled to the free amino acid thus obtained via its carboxy group, and thus the further amino acid residues of the peptide to be synthesized are coupled step by step in the appropriate order. After all the amino acids have been coupled, the finished peptide is separated from the support and, if appropriate, the further functional side groups are also cleaved off. The stepwise condensation is carried out with the corresponding, conventionally protected amino acids in a known manner. The coupling of the individual amino acids is carried out in the usual ways, where in particular the following methods can be considered: - the method of symmetrical anhydrides, dicyclohexylcarbodiimide (QIC) is the carbodiimide method in general, the carbodiimide-hydroxy-hexotriazole method (cf. E. Gross and J. Mei (eds.), "The peptides", vol. 2). Preferably, the racemization method is azide coupling, or the method using DCC / 1-hydroxybenzotriazole or DCC / 3-hydroxy-4-oxo3,4-dihydro-1,2,3-benzotriazole. Activated esters can also be used. Particularly suitable for the stepwise reaction of amino acids are the activated esters of protected amino acids, such as the N-hydroxysuccinimide ester or the 2,4-5-phosphine ester. Very suitable as catalysts for the amino reaction are those N-hydroxy compounds whose acidity is approximately the same as that of acetic acid, such as 1. The amino esters can be used with groups that can be removed by hydrogenation, such as benzyloxycarbonyl. (Zrt) or the weakly acidic group. The o-position amino groups are the tert-butyloxycarbonyl group, the flucrenylmethyloxycarbonyl benzoxy group, or the carbobenzothio group (optionally or p-nitrobenzyl group), the trifluoroacetyl group, the phthalyl group, the o-nitrophenoxyacetyl group,. the thio group, the p-thioluenesulfonyl group, the benzylic, benzylic substituted benzene ring (p-bromo- or p-nitrobenzylic isoform) and the o-phenylethyl group. These include Jesse P. Greenstein and Milton Winitz, “Chemistry of amino acids” (New York, 1961, John W. and Sons, Inc., vol. 2, e.g. p. 863), “Principles of peptide synthesis” (Springer Verlag, 1984), J. M. Stewart and 3. D. Young, Solid phase peptide synthesis” (Pierce Chem. Company, Rockford, Hl., 1984), G. Bárány and RB Merrifieíd , “The peptides” (1, chapter 1~ p. 285, 1979, Aeademlc Press Inc.), and E, Gross and J. Maienhofer (eds.)YThe peptide,(2.Volume 1, Aeademlc Press, New York). These protecting groups can in principle also serve to protect other functional groups (OH groups, NH3 groups) of the amino acids in question. Hydroxyl groups (serine, threonine) are preferably protected with benzyl groups and similar groups. Other non-α-amino groups (e.g. ω-amino groups or the guanidine group of arginine) are preferably protected with The individual amino acid building blocks, except for lysine or ornithine modified with the R-CO group, are commercially available. One possible reaction sequence for the preparation of the latter two compounds is as follows: 1) the α-carboxylic acid groups are amides. the ε-amir is protected, so that the amino group is protected S?a| j&mK? í 4) the Z-group is cleaved from the ε-amino group, 5) the desired R4-C'O group is attached to the ε-amino group, 6} the Boc group is cleaved from the o-amino group, 7) we attach the Z-group to the σ-amylno group. The introduction of the R'-CG-group is carried out by reaction of the amino group of lysine with the corresponding carboxylic acid, essentially according to the procedure mentioned above during the coupling of amino acids. However, the condensation using a carbodiimide, for example 1-ethyl-3-[3-dimethylaminopropionyl]-carbodiimide and 1-hydroxybenzotriazole is particularly preferred. The reaction of coupling the amino acids is carried out in a conventional inert solvent or suspension medium (e.g. dichloromethane), to which dimethylformamide may optionally be added to improve solubility. Insoluble polymers can be used as synthetic carriers, for example, polystyrene resin beads swellable in organic solvents (e.g., copolymers of polystyrene and 1% divinylbenzene). The construction of a protected dacapeptide amide on methylbenzhydrylamide resin (MBHA resin, i.e., a polystyrene resin with methylbenzhydrylamide groups), which process, after cleavage from the carrier with hydrogen fluoride, results in the desired C-terminal arm functionality of the peptide, is shown in the following flow chart: Flowchart Peptide synthesis protocol Step Operation Solvent / Reagent (v / v) Time 1 wash methanol 2x2 min 2 wash DÓM 3x3 min 3 cleavage DCM / TFA (1:1) 1x30 min 4 wash isopropanol 2x2 min 5 wash methanol 2x2 min 6 wash DCM 2x3 min 7 neutralization DCM / DIPEA (9:1) 3x5 min 8 wash methanol 2x2 min The Na-20-protected amino acids in a three-fold molar excess are usually coupled to each other in the presence of diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HO) in a mixture of CH2Cl2 and ZDMF for 90 minutes, and the Boc protecting group is cleaved by treatment with 50% trifluoroacetic acid (TFA) in dichloromethane for half an hour. The completeness of the reaction can be checked by the Chrisiensen chloranil test and the Kalser ninhydrin test. The remaining free amino group is blocked by acetylation with a fivefold amount of acetylimidazole in dichloromethane. The sequence of steps in the peptide synthesis on the resin is shown in the flow chart. To separate the resin-bound peptide, the final product of the solid phase synthesis was dried over P2O5 under reduced pressure, and then treated with a 500-fold excess of hydrogen fluoride / anisole (10:1 by volume) for 60 minutes at 0°C. After distillation of RF and azole under reduced pressure, the product is stirred in anhydrous ethyl ether, during which the peptide acid separates as a white precipitate. The peptide is cleaved from the polymer support by washing with 50% aqueous acetic acid. The acetic acid solution is gently evaporated under reduced pressure, yielding the peptide as a high viscosity oil, which, upon addition of anhydrous diethyl ether, transforms into a white precipitate at low temperature, Further purification can be performed by routine preparative high-pressure liquid chromatography (HPLC). π The conversion of the peptide into an acid salt can be carried out by an acid reaction in a known manner. In turn, free peptides can be obtained from acid addition salts by reacting the salt with a base. The peptide embonate can be prepared by the reaction of the trifluoroacetic acid salt (TFA salt) of the peptide and free embonic acid (pamoic acid) or the corresponding disodium salt of embonic acid. For this, an aqueous solution of the peptide TFA is mixed with a solution of disodium embonate in a polar-aprotic medium, preferably in dimethylacetamide, and the light yellow precipitate formed is recovered. The binding of the compounds of formula (I) according to the invention to the receptor was investigated. The method is largely based on that described by Beckers et al. [Eur. J. Biochem, 231: 535-543. p. (1995)]. Cetrorelix obtained by the syntheses disclosed herein is iodinated with the isotope [12Ί] (Amersham; specific activity 80.5 Bq / fmol), using IcdoGen reagent (Piarcé). The reaction mixture is purified by reversed-phase high-performance liquid chromatography, where monoiodinated Cetrorelix is ​​obtained without unlabeled peptide. About 80% of the f25lj-Cetrorelix and the unlabeled compound of the invention are suitable for specific receptor binding. The in vitro activity of the compounds of the invention can be tested by the following 2 methods: the binding ability is assessed by the [25I]-Cetrorelix assay (Method 1), while the functional activity is assessed by the assay using the agonist effect of Trypsin (Method 2). Method 1 Beokers 7., Marheineke K., Reinlander H., and Hilgard P. "Selection and characterization of mammalian cell lines with stable overexpression of human pituitary receptors for gonadotropin (GnRH)" (Eur. J. Biochem., 231; 535.-543. (1995)}. For receptor binding assays, Cetrorelix was iodinated with f21Q (Amersham; specific activity 80.5 Bq / µl) using the IodoGen reagent. The reaction mixture was purified by reversed-phase high-performance liquid chromatography, yielding monoiodinated Cetrorelix without unlabeled peptide. Approximately 80% of the [:25l-Cetrorelix was suitable for specific receptor binding. The receptor binding assay was performed with intact cells under physiological conditions as described by Beckers et al. (1995). Subconfluent cultures of LTK cells stably transformed to express the human LHRH receptor were incubated in NaCl / R (137 mmol / l NaCl, 2.7 mmol / l KCl, 5 mmol / l Na2HPO4, 11.47 mmol / l KH2PO4) / 1 mmol / l EDTA medium and harvested by centrifugation. The cell pellet is suspended in binding buffer (DMEM without H2CO3, 4.5 g / l glucose, 10 mmol / l Hepes, pH7.5, 0.5% (w / v) B3A, 1 g / l bacitracin, 0.1 g / l SBTI, 0 / 1 % (w / v) NaN3). For the displacement assay, 0.25x10® cells 1 / 100 µl of cell suspension are incubated with approximately 225 pmol / l f25ii-Cetrorelx (specific activity 5-10x10'1dpm / pmol) and various concentrations of the unlabeled compound of the invention as a competitor. The cell suspension in 100 µl of the growth medium is added to 200 µl of 84% silicone oil in 400 µl test tubes. (Merck Typ 550) and 16% by volume paraffin oil.The cells are incubated for 1 hour at 37°C with slow, continuous shaking and then centrifuged for 2 minutes at 9000 rpm (reiorope; HTA13.8; Heraeus Sepatec, Osterode / Germany), during which the cells separate from the incubation medium. The tip of the tube containing the cell pellet is cut off. The tip containing the cell pellet is finally counted by gamma-ray counting. The amount of non-specifically bound, including unlabeled Cetrorelix, is determined at a final concentration of 1 pmol / l. This is the total amount bound. EBDÁ / ligand analysis program emzoen < iO%~a. ram (Biosofl V3.0). Method 2 Functional test for studying antagonistic behavior The assay is performed with some modifications according to Seckers T., Rellánder H., Hílgard P., as described in the article “Characterization of gonadotropin-releasing hormone analogs based on a sensitive cellular luciferase reporter gene assay (Seckers et al.; Analyt Biochem., 251; 17-23 (1987)). Human LHRH receptor and TQGOO cells expressing a luciferase reporter gene are cultured in DMEM medium supplemented with additives and 1% (v / v) PCSr for 24 hours in a microtiter plate. Finally, the cells are stimulated with 1 nmol / l [D-Trp0] LHRH for 8 hours. The antagonist compounds of the invention are added to the suspension before stimulation, and finally the cells are lysed for quantitative measurement of the Luc activity of the cells. The IC50 value is calculated by determined from the dose / effect curve by non-linear regression analysis using the Hill model (C. Grunwald; Programm EDX 2.0; Arzneimíttelwerk Dresden). The quantification of Luc activity was performed essentially as described (Promega Technics! Bulletin #101 / 181) in duplicate using the given luciferase assay kit (Promega £4030). The oxidation of luciferylCoA occurs under favorable kinetic conditions by the addition of Coenzyme A (CoA). After removing the culture medium from the microtiter plate, the cells were lysed by adding 100 µl of lysis buffer (25 mM Tris-phosphate, pH 7.8, 2 mmol / l dithiothreitol, 2 mmol / l 1,2-diammon-1-cyclohexene-NsN,N:',N'-tetraacetic acid (CDTA), 10% (v / v) glycerol, 1% (v / v) Triton X-100). After 15 min incubation at room temperature, 10 µl of cell lysate was transferred to a white microtiter plate (Oynatech) suitable for luminometric detection. The enzymatic reaction was stopped in 50 µl of assay buffer (20 mM Tris).pH 7.8, 1.07 mmol / l (MgCOs^MgCOHjs, 2.87 mmol / l MöSOa, 0.1 mmol / l ethylene diamine tetraacetic acid (EDTA), 33.3 mmol / l dithiothreitol, 270 pmol / l Coenzyme A, 470 pmol / l firefly (Photinus pyralis) -luciferin, 530 pmol / l rATPNas) is added. After one minute, the luminescence is determined using an EG&G Berthold MIcroLumat L8 98 P device with appropriate parameters. Using this method, we obtain the following in vitro results, where Koa represents binding affinity and ICso represents functional activity, and pM represents the number of independent experiments in parentheses The following examples are provided to illustrate the invention. The examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Claims

Example 1 The synthesis was carried out according to the solid phase flow chart (peptide synthesis protocol, page 10ΤΙ.) by DIC / HÖBt coupling, starting from 3.3 g of MBHA resin (charge density 1.08 mmol / g). After HF cleavage from the polymer support, 3.4 g of crude peptide were obtained, which were purified by the usual preparative HPLC method. After final freeze-drying, 1.43 g of product, uniform according to HPLC, with the formula CsvHssNnOuCI were obtained. The FAB-TS measured; 1458.7 (M+H*), (calculated: 1457.7) value and the 1H-NMR spectrum was consistent with the structure. 1H-NMR (5GÖ MHz, Dsö / DMSO-de, δ in ppm): 8.7-7.2 (several m, aromatic H and not completely replaced HH); 6.92 and 6.58 (2d, 2x2H, aromatic H, p-Cl-Phe); 5.23.5 (several m, Co-H and aliphatic H); 3.2-2.6 (several m, aromatic Cp-H); 2.1-0.7 (several m, residual aliphatic H); 1.70 (s, 3H, acetyl group); 1.20 (d, 3H, Οβ-Η, Ala); 0.8 (m, C8H, Leu) Example 2 Ac-D-Nai<2)5-D-Cpa2-O-PaK3)3-Ser4-N-Me-Tyrs-D-Lys(B)8-Leu7~Lys <tPr)8Pro9-D-Ala'ö-NH2 A szintézist a szllárdfázis tdlyamatdiagram (peptídszintézís protokollja, ΙΟ11. old.) szerint végezzük, DIC / HÖBt-kapcsolással, 4,0 g MBHA-gyantábe! (töltés sűrűség 1,11 mmol / gj kiindulva. A polimer hordozóról való HF-os hasítás után 4,87 g nyers pepiidet kapunk, melyet a szokásos preparatív HPLC eljárással tisztítunk. A végső fagyasztvaszáritás után 0,93 g, HPLC szerint egységes terméket kapunk, amit A-amidino-feníl-amíno-A-oxo-vajsavval, BOR kapcsolőreagens jelenlétében a kívánt vegyüietté alakítunk. Egy újabb HPLC-as tisztítással 148 mg CgsHnsNtyOtsCI: osszegképíefü célvegyöletet kapunk.ESI-TS for: 1647.8 (M-fH*) (calcd: 1645.8) and the 1H-NMR spectrum is consistent with the structure, 'H-NMR (500 MHz, CMSO-dg, δ in ppm): 10.4 (s, 1H); 9.13 (s, 2H); 8.94 (s, 2H, NH of 4-amidmo-aniline); 8.8-7.35 (several m, aromatic H and NH); 7.22 and 7.18 (2d, 4H, aromatic H, (pCl)Pbe): 8.95 and 8.58 (2d, 4H, aromatic H, Tyr); 5.2-3.5 (several m, Ca~H and aliphatic H); 3.3-2.4 (several m, Οβ-Η and N-CHJ; 2.1-1.1 (several m, residual aliphatic H); 1.88 (s, 3H, acetyl group); 1.20 (d, 3H, Οβ-Η, Aia), 0.83 (dd, 6H, C8-H,. Example 3 The synthesis of Ao-D-Naí(2)1-D~Cpa2-D-Pal(3)s~Ser4-N~Me-Tyr'-D-Lys(B)6-Leu7-Args~Pro2-DA was carried out according to the solid phase flow diagram (peptide synthesis protocol, page 10ΤΙ.) by DIC / HQBf coupling, starting from 4.0 g of MBHA resin (charge density 0.97 mmol / g). After HF cleavage from the polymer support, 4.0 g of crude peptide was obtained, which was purified by the usual preparative HPLC method. After final freeze-drying, 1.39 g of a uniform product according to HPLC was obtained, which was converted to the desired compound with 4-amidino4phenylamino-4-oxobutyric acid in the presence of BOR coupling reagent. Further HPLC purification yielded 440 mg of the target compound with the molecular formula CgsH.6N-is6Cl. The ESI-TS measured; 1832.7 (M-rH) (calculated; 1631.7) and the 1 H-NMR spectrum was consistent with the structure.WNMR (500 MHz, DMSO-eU, δ in ppm): 10.4 ($, 1H); 9.15 (s, 2H); 9.0 (s, 2H, NH of 4-amidino-aniline); 8.8 (m, 2HS aromatic H); 8.3-7.2 (several m, aromatic H and NH); 7.27 and 7.20 (2d, 4H, aromatic H, (pCÍ)Phe); 6.96 and 8.80 (2d, 4H, aromatic H, Tyr); 5.2-3.5 (several m, Co-H and aliphatic H); 3.2-2.4 (several m, Οβ-Η and N-CHS); 2.13? 1.1 (several m, residual aliphatic H); 1.70 (s, 3H, acetyl group); 1.20 (d, 3H, Οβ~Η, Alá); 0.85 (dd, 8H, C8-H Leu). Example 4 Ao-D-Nal(2)'-D-Cpa2-D-Pal(3)3-Ser4-N-Me-Tyrs-D-Hc18-Nle7 Ala10-NH2 -Pro— The synthesis was carried out according to the solid phase flow chart (peptide synthesis protocol, p. 1011) by DIC / HOBt coupling, starting from 2.5 g of MBHA resin (charge density 1.08 mmol / g). After HF cleavage from the polymer support, 2.78 g of crude peptide were obtained, which were purified by the usual preparative HPLC method. After final freeze-drying, 400 mg of product were obtained, which was uniform according to HPLC as C?s.Hic2N15Ö:uCÍ. ESI-7S measured; 1472.8 (M+H*) (calcd. 1471.7) and the 1 H-NMR spectrum is consistent with the structure.(500 MHz, D2O / DMSO~dg, δ in ppm): 8.82 (m, 2H); 8.30 (m, 2H); 7.80 (m, 4H); 7.66 (s, 1H); 7.47 (m, 2H); 7.38 (d, 1H, aromatic H); 7.25 and 7.20 (2d, 4H, aromatic H, (pCí)Phe); 6.98 and 8.83 (2d, 4H, aromatic H, Tyr); 5.10-4.0 (several m, Co-H and aliphatic H); 3.75-2.85 (several m, Cp-H and N~CH3): 2.1-1.05 (several m, residual aliphatic H); 1.74 (s, 3H, acetyl group): 1.23 (d, 3H, Cp~H, Aia); 1.20 (m, CH3 Isoprop! powder); 0.8 (m, 3H, CS-K, Nle). ÁC“D~Nal(2)1~D-Cpa2-D~Pal(3)3~Ser4-N~Me~Tyrs-D~Hci6-Nle7~Lys(iPr)s~PrQsSar^-MHa The synthesis is carried out according to the solid phase main page 11) starting from 2.5 q MBHA-guanta (charge IS density 1.08 mmol / g) by DIC / HOSf(peptide synthesis Hassal). After HF cleavage from the polymer support, 2.74 g of crude peptide is obtained, which is purified by the usual preparative HPLC method. After the final freeze-drying, 840 mg of product with the uniform formula CysH'SösNísO^Ci according to HPLC is obtained.ESI-TS measured: 1472.8 (M+H*) (calcd: 1471.7) and the 'H-NMR spectrum is consistent with the structure. 'H-NMR (500 MHz, D2O / 'DMSÖ«d&í in 6 ppm): 8.8 (m, 2H); 8.3 (m, 2H); 7.85 (m, 2H); 7.8 (m, 2H); 7.65 (s, 1H); 7.76 (m, 2H); 7.35 (d, 1H, aromatic H); 7.23 and 7.17 (2d, 4H, aromatic H, (pCl)Phe); 7.0 and 8.8 (2d, 4H, aromatic H, Tyr); 5.103.8 (several m, Co-H and aliphatic H); 3.75-2.8 (several m, Cp-H and M~CH3); 2.2-1.05 (several m, residual aliphatic H); 1.70 (s, 3H, aoetHosoport); 1.23 (d, 3H, Οβ-Η, Ala); 1.20 (m, CK3 isopropitosoporf); 0.8 (m, 3H, C8-H Nle). 3-(4-Fluoro-phenyl)-propionyl-D-Nal(1)5~Ser4-N-Me-Tyr5-D-Lys(Atz)$-Leu7la' The synthesis was carried out according to the solid phase flow chart (peptide synthesis protocol, p. ΙΟ11), by DIC / MOBí coupling, starting from 9.2 g of MBHA resin (charge density 1.08 mmof / g), after HF cleavage from the polymer support. 5.8 g of crude peptide is obtained, which is purified by the usual preparative HPLC method. After final freeze-drying, 2.0 g of HPLC-identical, unsubstituted octapeptide is obtained, 0.4 mmol of which is reacted with 0.5 mmol of 3-amino-1,2,4-triazole-5-carboxylic acid in the presence of the PyBOP coupling reagent to obtain 790 mg of crude product. A further HFLC purification yields 200 mg of the desired compound as a yellow solid. ESI-TS measured: 1304.6 (PRH Ί (calculated: Ή-NMR (500 MHz, D2O / OMSO-ds, δ in ppm): 8.14 (m, ÍH); 7.90 (m, 1H>; 7.80 (m, 1H); 7.50 <m, 2H); 7,35 (m, 2H); 7,0 (m, 6H); 7,63 (m, 2H, aromás H); 5,0 (m, 1H): 4,83 Cm. I); 4,41 (m, 1H); 4,30-4,05 (több m, 4H, Ca-H> ; 3.86-2.25 (several m, aliphatic and aromatic side chain H); 2.95 (s) and 2.75 (s, 2.05-1.1 m, residual aliphatic H); 1.20 (d, Οβ-H, Aia); 0.75 (m, OH, C8~H, Leu). REQUIREMENTS 1.Compounds of general formula (I) and their salts with carboxylic acids, A-Xxx -Xxx Χχχ~-Χχχ^-ΧχχχχχχΚΧχχΑχχχΚχχΑχχΧ10„|\|Η·>íö Xxxz~} Xxx4 is acetyl- or 3-(4-fluorophenyl)-prcplonl is D~Nal(1) or D~Na!{2); is D-Cpa~D~Pal(3) or a single k is Ser; is N-Me-Tyr; is N-Me-Tyr; is Nic; is Arg or Lys Xxx' is Pro: and is Ala or Sar.

2. The compounds of claim 1, wherein the salt is an acetic acid, trifluoro; or 3, A compound of claim 1, having the formula: Ac-D-Nal(2)'-D~Cpa2-D-Pal(3}3-Ser4~N-Me-Tyr5~D-Hd6~tMle?-Arg8~Prö9-DAlá ''-ΝΗσ.

4. The compound according to claim 1, whose formula is: Αο-Ο-Ν3ΐ(2)!-Ο-Όρ3Λ-Ο-Ρ3ΐ(3)Λ-δβΓ-N-Me-Tyr'-D-Hcr-Nle -Lys(IPr) -Pro Ala1ö-NH2 The compound according to claim 1, the formula of which is: AO“D-Nal(2)1-D~Cpa2-OPal(3)3~Ser4“N-Me“Tyrs~D~Hcis~Nle7-Lys(iPr)s-ProsSar10-NH2.

6. The compound of claim 1, wherein the sequence is Ac-D-Nal(2)1~D~Cpa2~O~Ral<3)3~Ser4~H-Me-Tyr5-D~Hcíe~Nle7-Arg8-Pros ,w 7. A pharmaceutical composition comprising a compound according to one of claims 1-6. 3 A process for the preparation of a compound of general formula (!) according to claim 1, wherein fragments of the components of the general formula Xxxm - where m is an integer between 1 and 10, and Xxx1 acylated - provided with a suitable protecting group are built up on a solid phase or in solution by the usual method, finally the fragments are connected on the solid phase by segmental coupling, and after the coupling is completed, the compound of general formula (I) is separated from the solid phase by the usual salting-out method, with the addition of the building block Xxx'°.

9. Use of the compounds according to claims 1-6 for the preparation of medicaments for the treatment of hormone-dependent tumors, in particular prostate cancer or breast cancer, and non-malignant diseases requiring LHRH suppression.

10. A process for the preparation of medicaments, wherein the compounds according to claims 1-6 are mixed with the usual carriers and excipients, and the mixture is processed as a medicament.