PT84282B - PROCESS FOR THE PREPARATION OF BRADIQUININE ANTAGONIST PEPTIDES - Google Patents

Abstract

Modified bradykinin-type peptides of formula (I) and pharmaceutically acceptable salts are new A-Arg-B-C-D-W-X-Y-Z-Arg (I) where A=H, D- or L-amino acid residue, dipeptide or polypeptide contg. D- or L-amino acid residues, or an acyl, aromatic urethane or alkyl-type N-terminal protecting gp.; B=D-or L-Pro, or D- or L-cyclic aliphatic or opt. substd. aromatic acid residue; C=D- or L-Pro, or D- or L-cyclic, aliphatic or opt. substd. aromatic amino acid residue; D=Gly or L-aliphatic or opt. substd. aromatic amino acid residue; W=opt. substd. L-Phe, or L-aliphatic or opt. substd. aromatic amino acid residue; X=L-Ser, Gly or D- or L-aliphatic or opt. substd. aromatic amino acid residue; Y=D-aliphatic or opt. substd. aromatic amino acid residue; and Z=opt. substd. L-Phe or L-aliphatic or opt. substd. aromatic amino acid residue.

Description

«PROCESS FOR THE REPAIR OF 1'LPTI OF BRADIQUININE ANTAGONISTS”

FIELD OF THE INVENTION

The present invention relates to new biologically active peptides that act as antagonists of the biological activities of bradykinin alone; their therapeutically acceptable salts and their applications as therapeutic agents.

BACKGROUND OF THE INVENTION

Twenty-five years after the description and synthesis of the bradykinin peptide sequence, a potent mammalian vasodilator (Boisonnas et al., Experientia 16: 326, 1960), many hundreds of related peptide analogs have been synthesized and tested in biological systems with the if. bradykinin quoted earlier ^ Schroeder, in Handbook of Experimental Pharmacology, Vol. 25, (Springer Verlag) p. 324-350, 197θ7 Z ”Stewart, Handbook of Experimental Pharmacology, Vol. 25 (Supplement), (Springer Verlag) p. 227-272, 197 ^ 7. In these studies, the aim was to investigate the various physiological and pharmacological functions of bradykinin.

Bradykinin and the peptides calidine (Lys-bradykinin) and Met-Lys-bradykinin, which are physiologically important and related to it, contract smooth muscle (causing, for example, diarrhea and intestinal inflammation).

and asthma), decrease blood pressure, intervene in inflammatory processes such as allergies, arthritis and asthma, participate in the body in blood coagulation reactions and in reactions in which they intervene as a complement, intervene in rhinitis (viral, allergic and non-allergic) and they are produced in excess in pathological situations such as septic shock, acute pancreatitis, hereditary angioneurotic edema, depressive syndrome ("dumping") after a gastrectomy, carcinoid syndrome, anaphylactic shock, reduced sperm motility and some other situations. The production of bradykinin from pias ma causes pain in the pathologically affected area · excess production intensifies the pain directly or by stimulating bradykinin to activate the arachidonic acid cycle that produces prostaglandins and leukotrienes, the oldest and most effective mediators of inflammation, In Handbock of Experimental rharmacology, Vol. 25, Springer-Verlag, 1970 ® Vol 25 Supplement, 1979 »there are references to scientific works that describe these actions of bradykinin and related peptides.

As already mentioned, it was observed that bradykinin is produced in inflammatory reactions in the intestine causing contraction of smooth muscle and the secretion of fluid and ions.

In Nature, 229: 256-259 »19θ2, Líanning et al., Revealing the influence of bradykinin in very low concentrations, on fluid and ion secretion, demonstrated the existence of specific bradykinin receptors in the mucosal lining of the intestine and muscle intestinal smooth.

Kimura. et al .. in American Heart Journal

(85: 635-647, 1973) and Staszewska - Barczak et al .. in Cardiovascular Research (10: 314-327, 1976), reported studies on the production of bradykinin and the pain that accompanies it in angina. The action of bradykinin, mentioned above, and simultaneously the action of prostaglandins are the natural stimulus that causes the excitation of sensory receptors that signal pain during myocardial ischemia.

Bradykinin and related quinines are not only produced by the animal, but can also be injected through bites and bites. Insects such as hornets and wasps are known to inject bradykinin-related peptides that also cause pain, swelling and inflammation.

The absence of competitive and specific bradykinin antagonists related to its sequence has seriously impeded the understanding of the mechanism of action of bradykinin, essential for the development of diagnostic agents and therapeutic agents aimed at relieving the intense pain caused by the production, sometimes in excess, bradykinin.

Among compounds as diverse as analgesics and anti-inflammatory substances, a large number of non-selective, nonspecific and non-peptide antagonists have been described for one or more of the biological activities of bradykinin that act through the pros, taglandin and non directly on the biological receptors of bradykinin (Rocha e Silva, and Leme, Med. Exp. 8: 287, 1963). As an example, we can cite antihistamines (Gecse et al .. J. Pharm. Pharmacol. 21: 544, 1969) * antibodies against

-. 4 diquinina fGrez et al., I. J. Pharmacol. 29s 35, 1974) already derived from benzodiazepine (Leme e Rocha e Silva, Br. J. Pharmacol, 25: 50, 1965)? high molecular weight ethylene oxide polymers (Wilkens and Back, Arch. Intl. Pharmacodynam. 209: 305, 197 ^) 5 esters of gallic acid (Posati et al. «J. Agri.Food Chem. 18: 632, 1970 ) and serotonin inhibitors (Go makkon and Shimkovich, Bull. Exptl, Biol, Med, 80: 6, 1975). Neither of these compounds individually nor any class of compounds specifically inhibits bradykinin.

As substances with antagonistic action of bradykinin, heptyl esters of several substances have been presented, such as, for example, isolated basic amino acids such as Arg and Lys (Gecse, Adv. Exptl, Biol. Med. 7θί 5, 1976), the dipeptide him - Gly (Gecse et al .. Int. Aech, Allergy 41: 174, 1971), * analogs of fragments of peptides in C-terminal position of bradykinin such as Pro-Phe-Arg (Glaesson et al _t , Adv, Exptl. Med. Biol. 120Bs 691, 1979) · When verified in test systems with bradykinin and depending on the dose used, these substances prove to be weak and partial agonists / antagonists showing little specificity with regard to the inhibitory action of bradykinin.

There is information about damaged vascular tissue preparations that respond to bradykinin analogs that do not have the rest of Arg in the C-terminal position, but do not respond to bradykinin, so analogs of these bradykinins that do not have the amino acid Arg have been developed. 9, as antagonists of the non-physiological activity of bradykinin. These antagonists have no signifi

captive agonist effects similar to those of bradykinin, nor any antagonistic effect, on any of the response systems of quinines, physiologically significant (Regoli and Barabe, Pharmacol, Reys. 32: 1,1080).

A large number of bradykinin analogs that contain the 0-methyl ether of the Tyr remains at positions 5 and / or 8 have been described as producing a mixed agonist / antagonist action on the uterus isolated from galactosemic rats but not on the uterus. normal rats. This antagonism did not reproduce safely in these animals (Stewart and Woolley, in Hypotensive Feptides, Springer Verlag, pg. 23-33, 1966).

Other changes that have been produced in the bradykinin molecule are the addition of amino acids at the N-terminal end that affect the degree of enzymatic degradation of bradykinin in vivo.

bradykinin half-life in systemic circulation is less than 3C seconds (S, H. Ferreira is JR Vane, B ~, J «Pharmacol, Chemothorap. 30: 417, 1? 67) · A single passage through the circulation pulmonary effect causes a destruction of bradykinin between 98 and 99 ^ (J «Robljs ro, JW, Ryan and JM Stewart, Res, Commun, Pathol, Pharmacol. 6: 207, 1973), according to the anesthetized rat assessment by measuring the depressant effects of an agonist administered by intraaortic route (Iã), avoiding pulmonary circulation and intravenous route (IV), by means of the addition of remains of single basic sanino acids, such as, B-Arg-, D-Lys-, Lys- and double, such as, D-Lys-Lys- at the N-terminal end of the bra diquinin sequence, in vivo, the resistance of agonists is stimulated

from bradykinin to destruction by pulmonary kinase. Λ addition of the Lys-Lys dipeptide to the N-terminal end of the bradykinin agonists gives them, in vivo, a total resistance to destruction, with respect to the initial passage through the pulmonary circulation (Rohlero, Ryan and Stewart, Res. Gomm Pathol, Pharmacol, 6: 207, 1973).

SUMMARY OF THE INVENTION

The present invention relates to the modification of the sequence of bradykinin, a peptide hormone of the mammals (Arg-Pro-Pro-G-ly-Phe-Ser-Pro-Phe-Arg) and its acceptable salts pharmacist in the rest of Iro located in position 7, using an unusual method that for the first time produces analogs related to the bradykinin sequence, cited above, which act as competitive and specific inhibitors of the biological activities of bradykinin. The present invention relates specifically to the replacement of L-Pro at position 7 by aromatic amino acids with the D configuration, an exchange that converts bradykinin agonists to antagonists and includes additional modifications at other positions of a modified 7 position bradykinin antagonist which confer increased potency as an antagonist, resistance to enzymatic degradation and / or tissue specificity in relation to the bradykinin sequence containing an ami. noacid with the D configuration. More specifically, the present invention relates to peptides of the general formula

Formula I

A — Arg-B — C — D — W — X — Y — Z — Arg (θ 1 2345678 9) (position number) in which

A represents a hydrogen atom or a single acidic, basic, neutral or aromatic amino acid residue with the D or L eon figuration, such as, D-Arg, D-Lys or L-Thi or a terminal nitrogen atom protecting group of the aromatic acid-urethane or alkyl type enzyme or alternatively A represents a di- or polypeptide containing amino acids with the D or L configuration such as, for example, Lys-Lys, Met-Lys or Gly-Arg-Met-Lys;

B represents a remainder of L-Pro, or other non-cyclic or D- or L-cyclic aliphatic amino acid remainder, such as, the substituted L-aromatic or aromatic amino acid L-hydroxyproline oxy;

C represents a remainder of D- or L-Fro or another aromatic amino acid optionally substituted, aliphatic or cyclic with the D or L configuration;

D represents a remainder of Gly or another aliphatic or aromatic amino acid optionally substituted with the L configuration such as Ala;

W represents a remainder of Phe with the L configuration, substituted Phe or another aliphatic or aromatic amino acid such as, for example, Leu, p -2-thienyl-alanine (Thi) or 2-pyridyl-alanine (pal);

X represents a remainder of Being with the L, Gly configuration or another aliphatic or aromatic amino acid eventually substituted with the D or L configuration, such as, pCl-D-Phe

-8or D-Phe;

Y represents a remnant of aromatic amino acid with the D configuration or substituted aromatic amino acid as D-Phe, P - (2 — thienyl) —D — Ala (DThi), p- (2-pyridyl) -I) -Ala (l ) -Pal), P> -2-naphthyl-D-Ala (D-Nal), DHis, D-homo-Fhe (DhPhe), C-methyl-DTyr (DOJíT), D-alpha-phenyl-Gly (DPhg), DTrp, Dtyr or pCl-DPhe (CDF);

Z represents a remainder of Phe cj? the L configuration, of substituted Phe or of another aromatic or aliphatic amino acid such as, for example, Leu, Thi or Pal,

Preferred are compounds of formula I in which A represents a hydrogen atom, B and C each represent the amino acid Pro or Hyp, D represents the amino acid Gly, W and Z each represent the amino acid Phe or Thi, X represents the amino acid Ser and Y represents any amino acid with the D configuration.

The peptide salts of general formula I include salts derived from hydrochloric acid, trifluoroacetic acid and acetic acid as well as other pharmaceutically acceptable salts.

Tables I and II show the substitutions that can be made in bradykinin and the results of those substitutions. By substituting, as indicated, 0, 1, 2, 3, 5, 7 * 8 amino acid residues of bradykinin are obtained the preferred bradykinin antagonists.

»9 TABLE I

Substitutions in Antagonists of the. Bradykinin

DNal

Azt Azt DPNF Thz Thz DPhe Inip Inip DTyr DPro DPro DPal Pro Pro Allah DOMT

DThi

DAI a f

Pro— Phe — Arg

D Arg Thi Gly Thi Lys-Lys OMT DPhe OMT DLys-Lys Pal CDF Pal Phe, Thi GLF DN alj CLF PNF DPal PNF Nal DThi Nal

Thi = - (2-Thienyl) alanine

Pal = - (2-Pyridyl) alanine

Hyp = 4-Hydroxypro1in

Azt = Azetidine-2-carboxylic acid

Thz = Thiazolidine-2-.carboxylic acid

Inip-isonipecotic acid

OMT = O-methyltyrosine

CDF = para-chloro-D-dxphenylalanine

Nal = - (2-Naphthyl) -alanine

GLF = para-chloro-L-phenylalanine

PNF-to-nitrophenylalanine

Pro = 2,3-Dihydroproline

TABLE II

Characteristics of Bradykinin Antagonists

Changes that confer tissue selectivity

Critical change in relation to antagonistic action

enzyme resistance to potency

DETAILED DESCRIPTION

The synthesis of the peptides of general formula I, including derivatization, activation, coupling of protected amino acid residues and their purification and the analytical methods used in the identification and determination of purity are included in the General Part of Peptide Chemistry as des. written in Methoden der Organische Chemie ”Vol. 16, parts I and II, by Houben Weyl (197 * 0, X ^ for wet synthesis and in Solid Phase Peptide Synthesis” by Stewart and Young (1984) for synthesis by solid via the Merrifield method Any chemist with knowledge of peptide synthesis can synthesize the general formula I peptides using conventional wet methods or manual or automatic solid methods.

The symbols and abbreviations used for both amino acids, their derivatives and protecting groups and for peptides and their salts are those that are commonly used in the chemistry of peptides (Biochem. J ,, 126: 773, 1972, newspaper cited by reference ). For convenience, many abbreviations are defined in Table III. All remains of amino acids, except that of Gly, described in the description of the present invention in the non-claims, have the L configuration, unless otherwise specified

TABLE III ABBREVIATIONS DESIGNATING THE REMAINS OF ATINOACIDS

Aib - alpha-aminoisobutaric acid Azt - azetidine-2-carboxylic acid CDP - para-chloro-D-phenylalanine CLF - para-chloro-L-phenylalanine hPhe - homo-phenylalanine Hyp - 4-hydroxy-pro.line Tnip - isonipecotic acid MDY - O-methyl-D-tyrosine Nal - beta- (2-na.ftil) -alanine APro - 2,3-dehydroproline Pal - beta- (3-pyridyl) -alanine Phg - alpha-phenylglycine Sar - sarcosine Thi - beta- (2-thienyl) -alanine Thz - thiazolidine-2-carboxylic acid

(All other abbreviations comply with IUPAC for amino acid remains)

I

The following examples illustrate the

general formula I according to the present invention but do not limit it. For solid compounds all percentages and proportions are referred to by weight and volume when referring to liquid compounds.

Example 1

Preparation of Àrg-lro-Pro-Sly-rhe-Ser-DPhe-Phe-Arg (DPhe? -BK).

A mixture of 6.4 g (15 mKoles) of _t-butyloxycarbonyl- (g-paratoluene sulfonyl) ~ .arg / BOC-Arg (Tosjy and .183 mg (1.5 ruMoles) of Ν, Ν- diniethylaminopyridine in a mixture of 20 ml of dimethylformamide (DaF) and 125 ml of dichloromethane (DCJl). At room temperature, 15 g of hydroxymethyl-polystyrene-divinyl-bonzene (with 1 $ d © re, containing 0 , 74 mMole of the free hydroxy group per g of resin) and then 60 ml of a 0.25M solution of dichiolobexylcarbodiimide (DCC) in dichloromethane (DC11). The resulting suspension is stirred overnight at room temperature, filtered and the resin is washed with 3 x 6 ml ml of dichloromethane, 3 x 6 ml ml of methyl alcohol and resumed with 120 ml of dichloromethane The coupling of another portion of BOC-Arg (Tos) is carried out on the After filtration and washing of the resin, it is re-swollen with 120 ml of dichloromethane and 2.1 ml of benzoyl chloride and 1.5 ml of triethylam are added. The suspension is stirred for 3 minutes at room temperature, after which the resin is filtered, washed with 3 x 60 ml of dichloromethane, 3 x 60 ml of methyl alcohol and finally with 3x 60 ml of dichloromethane. Air dry the resin

to constant weight obtaining 18.5 g of BOC-Arg (Tos) -hydroxymethyl-resin with an amino acid content of 0.272 mmol of Arg per g of resin as determined by quantitatively analyzing the amino acid of a sample of the amino acid-resin complex which undergoes hydrolysis for 4 hours with the hydrochloric acid / N / propionic acid mixture, at a temperature of 130 ° C.

1.5 g of resin containing 0.4 mMole of Arg is introduced into the reactor of an automatic synthesizer (Beckman model 900) that operates solidly, submitting it to the following addition cycle to perform the BOC-Phe coupling :

PROGRAM A. STANDARD COUPLING WITH DICICLOHEXILCARBODIIMIDE (DCC)

The resin is washed with 3 x 20 ml of dichloromethane and then equilibrated for 1.5 minutes with 20 ml of a 1: 3 mixture of trifluoroacotic acid with dichloromethane containing 0.1% indole. The resin is rebalanced for 30 minutes. The resin is then washed with 6 x 20 ml of dichloromethane, neutralized with a 10% triethylamine solution in dichloromethane for 1.5 minutes after which the neutralization step is repeated again. The resin is washed with 6 x 20 ml of dichloromethane after which it is equilibrated for 1.5 minutes with a 1.0 mmole solution of BOC-Phe in dichloromethane. Then, 4 ml of 0.25 N dicyclohexylcarbodiimide in dichloromethane is added and the resulting reaction mixture is stirred. for 2 hours. The resin is then washed with 3 x 20 ml of dichloromethane.

According to Program B, a second addition cycle takes place:

PROGRAM B. REVERSE ADDITION:

The technique of Program A is repeated through neutralization followed by washing. 1.0 mMole of dicyclohexylcarbodiimide (DCC) in 4 ml of dichloromethane is then added and the resin and solution are stirred for 1.5 minutes. 1.0 mMole of BOC-D-Phe in 12 ml of dichloromethane is then added and the resin and solution are stirred for 2 hours. The resin was then washed with 6 x 20 ml of dichloromethane.

According to the following sequence, the nitrogen atom protecting group at the end is removed:

PROGRAM C. TERMINAL DEPROTECTION:

The PROGRAM A technique is repeated until neutralized with triethylamine. The resin is then washed with 6 X 20 ml of ethyl alcohol and the peptide resin complex is air-dried to obtain 1.66 g of D Phe-Phe-Arg-Resin in the form of a trifluoroacetic acid salt. . The synthesis is continued using 410 mg of DPhe-Phe-Arg-Resin as the salt of trifluoroacetic acid. According to PROGRAM D, the following rest is added.

PROGRAM D. REACOPLEMENT:

The peptide-resin complex is washed first in the form of a salt with 3 x 20 ml of dichloromethane, then neutralized for 1.5 minutes with 10% triethylamine in dichloromethane. The neutralization is then repeated and the peptide-resin complex is washed as a salt with 6 x 20 ml

- 16 dichloromethane. The peptide-re- (> sine complex is then equilibrated for 1.5 minutes with a 1.0 mMole BOC-Ser (OBzl) solution in dimethylformamide. Add 4 ml of dicyclohexylcarbodiimide (DCC) 0, 25 N and mixed with the resin for 2 hours · Wash the resulting product 3 times with dichloride> methane.

According to the specified Programs, the following amino acid divides were added to the growing peptide chain: BOC-Phe (A), BOC-Gly (á), BOC-Pro (a), BOC-Pro (A), following first, BOC-Pr · (d), BOC-Arg (Tos) re-coupled, dissolved in 2 ml of dimethylformamide and 9 ml of dichloromethane, and then Program C, 530 mg of the protected nonapeptide-resin complex are obtained , in the form of a salt derived from trifluoroacetic acid.

A 51θ mg suspension of the peptide-resin complex, mentioned above, is made in 10 ml of anhydrous liquid hydrofluoric acid containing 1 ml of anisole, at -70 ° C, and stirred for 45 minutes at 0 ° C. ° C. The hydrofluoric acid and anisole were removed in vacuo (water spout 1 hour, vacuum pump 1 hour), the peptide and resin were washed with 3 x 20 ml of ethyl ether and the peptide was extracted with 3 x 6 ml of glacial acetic acid. The acetic acid solution is lyophilized to obtain 185 mg of unprotected crude peptide.

The peptide was purified by countercurrent distribution (CCD) / 100 passages from the upper phase through an apparatus located after the column intended for countercurrent distribution (CCD_ £ 7 ⁱⁿ the n-butanol / trifluoroacetic acid system (1: 1) The contents of the tubes corresponding to the main peak that contain 17

have the peptide, quantitatively determined by the Sakaguchi reagent, evaporate the solvent under reduced pressure, dissolve the residue in glacial acetic acid and lyophilize to obtain 14 mg of peptide with a partition coefficient · (k) of 5.7 per countercurrent distribution. By repeating the counter-current distribution in the solvent system n-butanol / glacial acetic acid / water (4: 185), 73 mg of Arg-Pro-Gly-Phe- are obtained, following the detection process and the aforementioned technique. Ser-DPhe-Phe-Arg in the form of salt drift | trifluoroacetic acid (κ »0.2). Thin layer chromatography performed on glass plates coated with Merck silica gel using the solvent systems n-bu tanol / glacial acetic acid / water (8: 3: 4) and ethyl acetate / / pyridine / acetic acid glacial / water (5: 5sls3) provides in relation to the pure peptide an Rf (834) of 0.17 ® an Rf (5513) of 0.36 by visualization with the spray used in the identification of peptides and consisting of chloro-tolidine. A quantitative analysis using a Beckman 120 instrument and performed after acid hydrolysis (17 hours in closed glass ampoules under nitrogen at 110 ° C in 2 ml of 6N hydrochloric acid containing 2 drops of 2-mercaptoethanol and 40 µl phenol) provides the following amounts of amino acids: Arg (2.12) j Pro (1.93) y Gly (1.01); Phe (2.98); Ser (0.96).

Example 2

Preparation of Arg-Pro-Pro-Gly-Phe-Ser-DThi-Phe-Arg (DThi ^ -BK),

This peptide is prepared using the method described in Example 1 but used instead of BOC-DPhe, BOC-18

- β-2-thienyl-D-Ala (BOC-DThi): K (415) «0.24 ·, Arg (2.02), Pro (2.18), Gly (1.00), Phe (l , 99), Ser (o, 89), Thi (O, 99).

Example 3

Preparation of Arg-Pro-Pro-Gly-Phe-Ser-DPal-Phe-Arg (DPal ^ -BK).

This peptide is prepared by the method described in Example 1, using B0C-2-pyridyl-DAla (BOC-D-Pal) instead of BOC-DPhe: k (lil) «0,22j Arg (2,03), Pro (2.01), Gly (1.02), * Phe (1.99), Pal (1.02).

Example 4

Preparation of Arg-Pro-Pro-Gly-Phe-DPhe-DPhe-Phe-Arg (DPhe ^ _-BK).

This peptide is prepared by the method described in Example 1, using BOC-DPhe instead of BOC-Ser (Bzl): k (415) 1.3 Arg (2.12), Pro (1.94), Gly (1 , 00), Phe (3.94).

Example 5

I

Preparation of Arg-Pro-Pro-Gly-Phe-DPhe-CDF-Phe-Arg (DPhe ^ CDF ^ -BK).

This peptide is prepared by the method described in Example 1, using BOC-DPhe instead of BOC-Ser (Bzl) and BOC-p € lD-Phe (BOC-CDF) instead of BOC-DPhe: k (415) · 0.82; Arg (1.98), Pro (1.93), Gly (0.97), Phe (3.10), CDF (1.02).

Example 6

Preparation of Arg-Pro-Pro-Gly-Thi-Ser-DPhe- 19

-Thi-Arg (Thi ^ gDPhey-BK).

This peptide is prepared by the method described in Example 1, using BOC-2-thienyl-Ala (BOC-Thi) in the two addition cycles instead of BOC-Phe: k (415) = 0.21; Arg (1.98), Pro (1.94), Gly (1.04), Phe (1.04), Ser (0.96), Thi (2.05).

Example 7

Preparation of Arg-Pro-Pro-Gly-Thi-Ser-DThi-Thi-Arg (Thi ^ gDThiy-BK).

This peptide is prepared by the method described in Example 6, using BOC-DThi instead of BOC-DPheík (415) - 018; Arg (2.07), Pro (2.08), Gly (1.00), Ser (o, 93), Thi (2.88).

Example 8

Preparation of Arg-Pro-Pro-Gly-Thi-Ser-DPal-Thi-Arg (Thi ₅ gDPaly-BK).

This peptide is prepared by the method described in Example 6, using BOC-DPal instead of BOC-DPhe: k (lil) 0.15; Arg (2.00), Pro (2.20), Gly (1.09), Ser (0.89), Thi (1.92), Pal (0.89).

Example 9

Preparation of Arg-Pro-Pro-Gly-Thi-DPhe-CDF-Thl-Arg (Th ± ₅ gDPhe ^ CDF ^ -BK),

This peptide is prepared by the method described in Example 5, using BOC-Thi in the two addition cycles instead of BOC-Phe: k (415) «0.75? Arg (1.89), Pro (2.08), Gly (1.06), Phe (1.02), Thi (1.88), CDF (1.07).

Example 10

Preparation of DArg-Arg-Pro-Pro-Gly-Phe-Ser-DPhe-Phe-Arg (DArgQDPhe ^ -BK).

This peptide is prepared by the method described in Example 1, except that an additional cycle is carried out using BOC- (TOS) -DArg with Program A followed by terminal deprotection with Program C: k (l: l) « 3.55} Arg (2.89), Pro (2.07), Gly (1.02), Phe (3, O5), Ser (o, 98).

Example 11

Preparation of DArg-Arg-Bro-DPro-Gly-Phe-Ser-DPhe-Phe-Arg (DArg _Q Pro ^ DPhe ^ -BK).

This peptide is prepared descrjL to the procedure in Example 10, using Boc-DPro instead of BOC-Pro upon first adding this K (415) 0.15 ^s; Arg (3.12); Pro (1.90), Gly (1.05), Phe (3, O2), Ser (o, 92).

Example 12

Preparation of Arg-Pro-DPro-Gly-Thi-DPhe-CDF-Thi-Arg (DPro ^ Th ^ gDPhe ^ CDF ^ -BK).

This peptide is prepared by the method described in Example 9, using BOC-DPro instead of BOC-Pro when first added: k (415) ^and 0.18; Arg (2.00), Pro (1.98), Gly (1.04), Phe (0.99), Thi (1.89), PCF (1.11).

Example 13

Preparation of Lys-Lys-Arg-Pro-Pro-Gly-Phe-Ser-DPhe-Phe-Arg (Lys-Lys-DPhe ^ «BK).

This peptide is prepared by the method described in Example 1, except that two more addition cycles are performed with BOC- (e-ClZ) Lys, the first with Program D and the second with Program A followed by Program C: k (1: 1) = »0.52; Arg (2.04), Pro (1.99), Gly (o, 9o), Phe (3.00), Ser (o, 96),

Lys (2.01).

Example 14

Preparation of Lys-Lys-Arg-Pro-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (Lys-Lys-Thi ^ _g DPhey-BK).

This peptide is prepared by the method described in Example 13, using BOC-Thi instead of BOC-Phe in the two addition cycles of BOC-Phe: k (1; 1) = 0.33; Arg (1, 98), Pro (1, 97), Gly (1, 01), Phe (1, 03), Ser (0.97), Thi (1, 9), Lys (2.08).

Example 15

Preparation of DArg-Arg-Pro-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (DArg _Q Thi ₅ gDPhey-BK).

This peptide is prepared by the method described in Example 6, except that with Program D one more cycle of addition is performed with BOC- (Tos) DArg, followed by Program C: k (l: l) X 2.33; Arg (3.00), Pro (1.99), Gly (0.9), Phe (0.99), Ser (0.95), Thi (2.11).

Example 16

Preparation of DArg-Arg-Pro-DPro-Gly-Thi-Ser-DPhe-Thi-Arg (DAr _{g ()} DPro, jThi _{5 g} DPhey-BK).

This peptide is produced by the method described in Example 15, using BOC-DPro instead of BOC-Pro in the first addition: k (415) = 0.22; Arg (2, io), Pro (1, 9O), Gly (1, 05),

Phe (0.98), Ser (O, 94), Thi (1.96).

Example 17

Preparation of Lys-Lys-Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg- (Lys-Lys-Hyp ^ DPhey-BK),

This peptide is prepared by the method described in Example 13, using B0C- (4-hydroxy) -Pro (BOC-Hyp) instead of BOC-Pro in the first addition of this: k (l: l) = 0.35 ? Arg (2.00), Pro (1.03), Gly (1.00), Phe (3, O8), Ser (0.94), Lys (1.95), Hyp (1.01).

Example 18

Preparation of Arg-Hyp-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (HypgThi ^ gDPhey-BK).

This peptide is prepared by the method described in Example 6, using BOC-Hyp instead of BOC-Pro when the second addition is made, including re-coupling with Program D: k (l: l) «2.45; Arg (2.03), Pro (0.98), Gly (1.0, O), Phe (1.05), Ser (0.95), Thi (1.97), Hyp (0.95).

Example 19

Preparation of Lys-Lys-Arg-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (Lys-Lys-Hyp ^ Thi ^ gDPhey-BK).

This peptide is prepared by the method described in Example 18, except that two more addition cycles are performed with BOC- (e-ClZ) Lys, the first with Program D and the second with Program A followed by Program C: k (1: 1) = 0.27; Arg (2.07)? Pro (0.92), Gly (o, 99), Phe (1.03), Ser (o, 93), Thi (1.92), Lys (2.06), Hyp (1.10).

- 23 Example 20

Preparation of Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (Hyp ₃ Th ± ₅ gDPhe ^ BK).

This peptide is prepared by the method described in Example 6, using BOC-Hyp instead of BOC-Pro in the first addition: k (l: l) = 2.23 $ Arg (2.08), ΡΓο (θ, 9θ ), Gly (1.04), Phe (1.01), Ser (0.99), Thi (1.95), Hyp (0.94).

Example 21 (Preparation of DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (DArg _Q -Hyp ₃ Thi ₅ gDPhe ^ BK).

This peptide is prepared by the method described in Example 20, carrying out with Program D another cycle of addition with BOC- (Tos) DArg, followed by Program C: k (l: l) ® = 0.18 $ Arg (3 , 01), Pro (1.02), Gly (0.98), Phe (1.02), Ser (0.92), Thi (2.07), Hyp (0.97).

Example 22

Preparation of Arg-Hyp-Hyp-Gly-Thi-Ser-DPheI -Thi-Arg (Hyp ₂ , ₃ Thi ₅ gDPhe ^ BK).

This peptide is prepared by the method described in Example 6, using BOC-Hyp instead of BOC-Pro in the cycles in which the latter was used: k (l: l) = 1.56 $ Arg (2, o4), Gly (l, 06), Phe (l, 02), Ser (l, 01), Thi (l, 9 ^), Hyp (l, 93).

Example 23

Preparation of Arg-Hyp-Hyp-Gly-Thi-DPhe-CDF-Thi-Arg (Hyp _{2 3} Th ± ₃ gDPhe ^ CDF ^ -BK).

This peptide is prepared by the method described in Example 9, using BOC-Hyp instead of BOC-Pro in the cycles where the latter was used: k (415) - 0.89; Arg (2.06), Gly (1.00), Phe (1.03), PCF (1.05), Thi (1.92), Hyp (1.93).

Example 24

Preparation of Arg-Pro-Pro-Gly-Leu-Gly-DPhe-Leu-Arg (Gly ^ Leu ^ gDPhe ^ -BK).

This peptide is prepared by the method described in Example 1, using BOC-Leu instead of BOC-Phe in the cycles in which the latter was used and BOC-Gly instead of BOC- (OBzl) Ser: k (415) = 0 , 30; Arg (2, o4), Pro (2.05), Gly (1.98), Phe (0.98), Leu (1.95).

Examples 25 to 103

In the following examples, which are not limiting, very similar substituted peptides are prepared using methods identical to those cited above:

25 · Arg-Pro-Pro-Gly-Phe-Ser-DNal-Phe-Arg- (DNal ^ -BK.): K (415) = 0.37; Arg (2.09), Pro (2.02), Gly (o, 98), Phe (2.0 O), Ser (o, 96), Nal (0.95).

26. Arg-Pro-Pro-Gly-Phe-Ser-MDY-Phe-Arg (MDY ^ BK): k (1: 1) = »4.88; Arg (2.10), Pro (1.91), Gly (o, 9u), Phe (2.08), Ser (o, 94), MDY (1, O4).

27. Arg-Pro-Pro-Gly-Phe-Ser-DPhg-Phe-Arg (DPhg ^ -BK): k (1: 1) «* 3.55; Arg (2.01), Pro (1.90), Gly (1.03), Phe (2.07), Ser (o, 99), Phg (o, 98).

28. Arg-Pro-Pro-Gly-Phe-Ser-DHis-Phe-Arg (DHis ^ -BK): k (1: 1) = '0.30; Arg (2.04), Pro (2, O9), Gly (O, 94), Phe (2.00), Ser (1.00),

- 25 His (o, 93).

29, Arg-Pro-Pro-Gly-Phe-Ser-DTrp-Phe-Arg (DTrp ^ -BK) t k (415)

- 0.30; Arg (2.04), Pro (1.95), Gly (1.02), Phe (2.05), Ser (O, 95), Trp (o, 9O).

30. Arg-Pro-Pro-Gly-Phe-Ser-DTyr-Phe-Arg (DTyr ^ -BK) »k (lxl) = 2.70; Arg (1, 94), Pro (1, 88), Gly (1, 04), Phe (2, io), Ser (o, 97), Tyr (1, 08).

31 · Arg-Pro-Pro-Gly-Phe-Ser-DhPhe-Phe-Arg (DhPhe ^ -BK) x k (415) = 0.37; Arg (1.99), Pro (1.94), Gly (0.97), Phe (2.02), Ser (0.88), hPhe (1.20).

32. Arg-Pro-Pro-Gly-Phe-DPhe-DThi-Phe-Arg (DPhegDThi - ^ - BK) x k (415) »0.59; Arg (2.14), Pro (1.87), Gly (1.OO), Phe (3.01), Thi (O, 98).

33. Arg-Pro-Pro-Gly-Phe-DThi-DThi-Phe-Arg- (DThi ^ _? -BK) xk (415) «0.54; Arg (2.04), Pro (2.00), Gly (1.01), Phe (2.04), Thi (1.91).

34. Arg-Pro-Pro-Gly-Phe-DPhe-DNal-Phe-Arg (DPhe ^ DNal ^ -BK) x | k (415) - 1.04; Arg (2.02), Pro (2.04), Gly (1.01), Phe (2.94),

Nal (0.99).

35. Arg-Pro-Pro-Gly-Phe-DPhe-MDY-Phe-Arg (DPhe ^ MDY ^ -BK) x k (415) 'Q59; Arg (2.11), Pro (1.90), Gly (0.97), Phe (3.02), MDY (1.01).

36. Arg-Pro-Pro-Gly-Phe-DPhe-DPal-Phe-Arg (DPhe ^ DPal ^ -BK) x k (415) = 0.16; Arg (1.86), Pro (2.12), Gly (1.07), Phe (2.9o), Pal (1.05).

37. Arg-Pro-Pro-Gly-Phe-Gly-DVal-Phe-Arg (Gly ^ DVal ^ -BK):

k (415) · 0.20; Arg (2.08), Pro (2.00), Gly (1.95), Phe (1.98), Val (0.98).

38. Arg-Hyp-Pro-Gly-Phe-Ser-DPhe-Phe-Arg (HypgDPhe ^ -BK): k (ltl) = 3.76; Arg (2.00), Pro (0.93), Gly (1.02), Phe (3.16), Ser (O, 94), Hyp (o, 94).

39 »Arg-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg (Hyp ^ DPhe ^ -BK): k (lill) = 3.35; Arg (1.96), Pro (0.97), Gly (1.01), Phe (3.10), Ser (0.94), Hyp (1.02).

40. Arg-Hyp-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg (Hyp „_DPhe_-BK):

> J 7 k (l: l) = 2.33; Arg (2.03), Gly (1.02), Phe (3.10), Ser (o, 94), Hyp (1.91).

41. Arg-Pro-Pro-Gly-Thi-DPhe-DPhe-Thi-Arg (ThÍ _and ô ^Dph ® «) ·. · 5 9 θ * θ 9 I

42. Arg-Pro-Pro-Gly-Thi-DThi-DThi-Thi-Arg (Thi ^ gDThig _? -BK): k (415) «0.37; Arg (2.08), Pro (2.08), Gly (0.99), Thi (3.86).

43. Arg-Pro-Pro-Gly-Thi-DThi-DPal-Thi-Arg (Th ± _{5 g} DThi ₆ DPal ₇ -BK): k (lxl) = 0.70; Arg (1.93), Pro (2.11),

Gly (1.08), Thi (2.86), Pal (1.02).

44. Arg-Pro-Pro-Gly-Thi-DThi-DNal-Thi-Arg (Thi ^ gDThigDNal ^ BK) s k (415) = 0.59; Arg (2.19), Pro (2.08), Gly (1.00), Nal (0.93), Thi (2.88).

45. Arg-Pro-Pro-Gly-Thi-DThi-CDF-Thi-Arg (Thi ^ gDThi ^ CDF ^ -ΒΚ) k (415) «0.54; Arg (2.16), Pro (1.97), Gly (1.00), PCF (1.06), Thi (2.81).

46. Arg-Pro-Pro-Gly-Thi-DPhe-DAla-Thl-Arg (Thi ^ gDPhegDAla ^ -BK) ·. k (415) «0.32; Ârg (2.06), Pro (1.89), Gly (0.97), Phe (1.02), Ala (0.96), Th ± (2.12).

47. Arg-Pro-Pro-Gly-Thi-CDF-DAla-Thi-Arg (Thi ^ gCDF ^ DAla? -

BK): k (415) '0.39; Arg (1.96), Pro (1.93), Gly (1.00), Ala (0.99), Thi (2, O5), PCF (1, O8).

48. Thi-Arg-Pro-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (ΤΙιίθ-ΤΙιΙ ^ gDPh® ₇ -BK): k (415) «0.27; Arg (2.16), Pro (1.89), Gly (1.03), Phe (1.04), Ser (0.93), Thi (2.95).

49. DArg-Arg-Pro-Pro-Gly-Phe-Ser-DPhg-Phe-Arg (DArgQ-DPhg? BK): k (líl) «2.03; Arg (3, O5), Pro (2.00), Gly (o, 97), Phe (2.04), Ser (0.94), Phg (1, OO).

50. DArg-Arg-Pro-Pro-Gly-Phe-Ser-DTrp-Phe-Arg (DArgQ-DTrp? BK): k (1: 1) «4.88; Arg (3, O7), Pro (1.99), Gly (1.00), Phe (2, O4), Ser (0.89), Trp (O, 97).

51. DArg-Arg-Pro-Pro-Gly-Phe-Ser-DTyr-Phe-Arg (DArg ^ -DTyr ^ BK) j k (ltl) = 1.56; Arg (2.96), Pro (2.09), Gly (1.03), Phe (1.99), Ser (0.90), Tyr (1.04).

52. DArg-Arg-Pro-Pro-Gly-Phe-Ser-DHis-Phe-Arg (DArg ^ -DHis ^ ΒΚ): k (lil) - 0.18; Arg (3, O8), Pro (1.99), Gly (1.02), Phe (2.07), Ser (O, 89), His (O, 96).

53. DArg-Arg-Pro-Pro-Gly-Phe-Ser-DhPhe-Phe ~ Arg (DArgg-

DhPhe ₇ -BK) k (415) «0.18; Arg (3.06), Pro (1.98), Gly (0.95), Phe (2.05), Ser (0.86), DhPhe (1.11).

54. Lys-Lys-Arg-Pro-Pro-Gly-Phe-Ser-DPhe-Phe-Arg (Lys-LysDPhe ₇ -BK): k (l; l) 0.52; Arg (2.04), Pro (2.01), Gly (0.96), Phe (3.00), Ser (O, 96).

55. Lys-Lys-Arg-Pro-Pro-Gly-Phe-Ser-DTrp-Phe-Arg (Lys-LysDTrp ₇ -BK): k (ltl) = 0.67; Arg (2.01), Pro (2.00), Gly (1.01),

- 2 ₈ -

Phe (2.03), Ser (0.91), Ττρ (θ, 88), Lys (2, O3).

56. Lys-Lys-Arg-Pro-Pro-Gly-Phe-Ser-DTyr-Phe-Arg (Lys-LysDTyr ₇ -BK) tk (líl) = 0.21; Arg (2.01), Pro (2.11), Gly (0.99), Phe (2.02), Ser (0.97), Tyr (1.02), Lys (1.90).

57. Lys-Lys-Arg-Pro-Pro-Gly-Phe-Ser-DHis-Phe-Arg (Lys-LysDHís ₇ -BK) k (1: 1) «0.08; Arg (1.91), Pro (2.06), Gly (0.94), Phe (2.08), Ser (0.93), His (0.95), Lys (2.12).

58. Lys-Lys-Arg-Pro-Pro-Gly-Phe-Ser-DhPhe-Phe-Arg (Lys-LysDhPhe ₇ -BK): k (1: 1) = 1.13; Arg (1.99), Pro (1.93), Gly (0.98), Phe (2.06), Ser (0.92), DhPhe (1.11), Lys (2.01).

59. Arg-Pro-DPro-Gly-Phe-Ser-DPhe-Phe-Arg (DPro ^ DPhe ₇ -BK): k (415) = 0.27; Arg (2.07), Pro (1.97), Gly (O, 98), Phe (3.02), Ser (O, 95).

60. Arg-Pro-DPro-Gly-Phe-CDF-DAla-Phe-Arg (DPro ^ CDFgDAla, ^ BK): k (415) = 0.59; Arg (1, 99), Pro (2.03), Gly (o, 97), Phe (2.02), Ala (O, 99), PCF (1, O2),

61. Arg-Pro-DPro-Gly-Thi-Ser-DPhe-Thi-Arg (DPro ^ Thi ^ _g DPhe ₇ -BK): k (415) = 0.22j Arg (2, io), Pro (1, 96), Gly (l, 05), Phe (O, 98), Ser (o, 94), Thi (l, 9O).

62. DArg-Arg-Pro-Pro-Gly-Thi-DPhe-DAla-Thi-Arg (DArg _Q -

Th ± _{5 g} DPhe ₆ DAla ₇ -BK) k (lily) = 4.00; Arg (2.89), Pro (1.95), Gly (1.03), Phe (0.98), Ala (1.01), Thi (2.14).

63. DArg-Arg-Pro-Pro-Gly-Thi-CDF-DAla-Thi-Arg (DArgQThi ₅ , ₈ CDF ₆ DAla ₇ -BK) sk (415) «0.19; Arg (3.00), Pro (1.99), Gly (1.00), Ala (0.96), Thi (2.03), PCF (1.02).

64. DArg-Arg-Hyp-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (DArg ₀ Hyp ₂ Thi ^^ gDPhe ^ -BK): k (ltl) «= 1.50? Arg (3, 11),

Pro (o, 97), Gly (l, 03), Phe (l, o4), Ser (o, 95), Thi (l, 88),

Hyp (1.02).

65. DArg-Arg-Hyp-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (DArg ^ Hyp ₂ , ₃ Thi ₅ , ₈ DPhe ₇ -BK): k (1: 1) = 0.96; Arg (3.19), Gly (0.97), Phe (0.98), Ser (1, OO), Thi (1.95), Hyp (1.90).

66, Thi-Arg-Hyp-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (Τ1ι ± θ-

Hyp ₂ Thi _{5 g} DPhe ₇ -BK)

67. Thi-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (Τΐιίθ-

Hyp ^ Thl ^ θ DPhe ₇ -BK)

68. Thi-Arg-Hyp-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (Thi _Q -

Hyp ₂ , ₃ Thi ₅ , gDPhe _? -BK)

69. Arg-Hyp-Pro-Gly-Thi-DPhe-CDF-Thi-Arg (HypgThi-gDPhe-CDF ₇ -BK) k (415) = 1.04; Arg (2.02), Pro (1.01), Gly (1.0, OO), Phe (1.01), PCF (1.09), Thi (1.89), Hyp (O, 98)

70. Arg-Pro-Hyp-Gly-Thi-DPhe-CDF-Thi-Arg (Hyp ₃ Thi _{5 g} DPhe ₆ CDF ₇ -BK): k (ltl) «0.96 ·, Arg (2.01), Pro (l, ll), Gly (o, 97), Phe (l, 06), Th ± (l, 86), PCF (l, 06), Hyp (o, 95)

71. Arg-Hyp-DPro-Gly-Thi-DPhe-CDF-Thi-Arg (Hyp ₂ Pro ₃ Th ± ₅ , θ DPhe ₆ CDF ₇ -BK)

72. Lys-Lys-Arg-Hyp-Pro-Gly-Phe-Ser-DPhe-Phe-Arg (Lys-Lys-

Hyp ₂ DPhe ₇ -BK) k (lsl) = 0.37, Arg (1.99), Pro (0.96), Gly (O, 99), Phe (3.13), Ser (0.94) , Hyp (0.98), Lys (2.00)

73. Lys-Lys-Arg-Hyp-Hyp-Gly-Phe-Ser-DPhe «.Phe-Arg (Lys-LysHyp _2j3 DPhe ₇ -BK); k (l: l) = 0.28; Arg (2.03>, Gly (o, 95), Ser (o, 9 ^ ·), Phe (3, O8), Lys (2.08), Hyp (l, 92)

74. Lya-Lya-Arg-Pro-Pro-Gly-Thi-Ser-DThi-Thi-Arg (Lys-LysThi ,. gDThi ^ -BK): k (líl) «0.22; Arg (2.07), Pro (2.01), Gly (1.04), Ser (0.89), Thi (3.02), Lys (1.96)

75. Lys-Ly & Arg-Pro-Pro-Gly-Thi-Ser-DPal-Thi-Arg (Lys-LysTh ± ₅ gDPal ^ -BK): k (ltl) = 0.06; Arg (2.12), Pro (1.94), Gly (1.01), Ser (0.87), Thi (1.81), Pal (0.98), Lys (2.22)

76. Lys-Lys-Arg-Pro-Pro-Gly-Thi-DPhe-CDF-Thi-Arg (Lys-LysThl ^^ g DPhe ₆ CDF ₇ -BK): k (415) «0.11? Arg (2.02), Pro (2.00), Gly (1.02), Phe (1.00), PCF (1.06), Th ± (1.85), Lys (2.06)

77 · Lys-Lys-Arg-Pro-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (Lys-LysHyp ₃ Th ± ₅ , gDPhe ₇ -BK): k (lsl) «0.22; Arg (2, O5), Pro (0.96), Gly (l, 04), Phe (l, 03), Ser (O, 94), Hyp (l, 10), Thi (l, 84), Lys (2.04)

78. Lys-Lya-Arg-Hyp-Hyp-Gly-Thi-Ser-DPhe-Thi-Arg (Lys-LysHyp _{2 3} Th ± _{5 g} DPhe ₇ -BK): k (ly) = 0.15; Arg (2.00), Pro (2.06), Gly (1.01), Phe (1.03), Ser (O, 94), Thi (1.92), Hyp (2.04)

79 · Lys-Lya-Arg-Hyp-Pro-Gly-Thi-DPhe-CDF-Thi-Arg (lya-LysHyp ₂ Thi _{5 g} DPhe ₆ CDF ₇ -BK): k (l: l) »6.69? Arg (l, 96), Pro (l, 14), Gly (O, 96), Phe (l, 03), Thi (l, 77), PCP (l, o6), Lys (l, 93), Hyp (1:14)

80. Lys-Lys-Arg-Pro-Hyp-Gly-Thi-DPhe-CDF-Thi-Arg (Lya-LyaHyp ₃ Thi _{5 g} DPhe ₆ CDF ₇ -BK): k (lsl) = 6.14; Arg (2.04), Pro (0.97), Gly (1.01), Phe (o, 98), PCF (1.06), Thi (1.89), Hyp (1.01), Lys (2.05)

81. Lys-Lya-Arg-Hyp-Hyp-Gly-Thi-DPhe-CDF-Thi-Arg (Lya-LyaHyp _{2 3} Th ± _{5 g} DPhe ₆ CDF ₇ -BK): k (lill) = 4.88; Arg (2.02), Gly (o, 99), Phe (0.9é), PCF (1.1O), Thi (1.84), Hyp (2.01), Lys (2.06)

- 31 Α »

82. Arg-Thz-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (ThZgThi ^ gDPhe? -

BK): k (415) = 0.24; Arg (1, 97), Pro (1, 04), Gly (1, 02),

Phe (l, 06), Thi (l, 91)

83. Arg-Pro-Thz-Gly-Thi-Ser-DPhe-Thi-Arg (Thz ^ Thi ^ gDPhe? BK); k (ljl) = 5.25

84. Arg-Thz-Thz-Gly-Thi-Ser-DPhe-Thi-Arg (Thz _{£ 3} Th ± ₅ , _g DPhe ₇ -BK):

= 6.69

85. Arg-Aib-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (AibgThi ^ gDPhe? -

BK) í k (415) «0.18

86. Arg-Pro-Aib-Gly-Thi-Ser-DPhe-Thi-Arg (Aib ^ Thi ^ gDPhe ^ -

BK) s k (415) '0.24; Arg (2.09), Pro (0.99), Gly (1.05),

Ser (o, 95), Phe (l, 07), Thl (l, 94), Aib (o, 91)

87. Ar g-Aib-Aib-Gly-Thi-Ser-DPhe-Thi-Arg (Aib _{2 3} Ihi _5j gDPhe ₇ -BK): k (415) = 4.00

88. Arg-Azt-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (AztgThi ^ gDPhe ^ -

BK): k (415) = 0.18; Arg (2.07), Pro (0.99), Gly (1.02), Phe (1.04), Ser (0.95), Thi (1.97), Azt (o, 99)

I 89. Arg-Pro-Azt-Gly-Thi-Ser-DPhe-Thi-Arg (Azt ^ Thi ^ gDPhe? BK)

90. Arg-Azt-Azt-Gly-Thi-Ser-DPhe-Thi-Arg (Azt _{2 3} Th ± ₅ gDPhe ^ -BK)

91. Arg-Inip-Pro-Gly-Thi-Ser-DPhe-Thi-Arg (lnip ₂ Thi ₅ gDPhe ^ -BK): k (415) «0.21

92. Arg-Pro-Inip-Gly-Thi-Ser-DPhe-Thi-Arg (lnip ₃ Thi ₅ , gDPhe ₇ -BK): k (415) «0.18; Arg (2.10), Pro (0.95),

Gly (l, 04), Phe (l, 03), Ser (O, 93), Thi (l, 95)

93. Arg-Inip-Tnip-Gly-Thi-Ser-DPhe-Thi-Arg (lnip ₂ , ₃ Thi ₅ , _g DPhe ₇ -BK): k (415) =

0.18

94. Arg-Pro-Pro-Gly-Thi-Ser-DNal-Thi-Arg (Thi ^ gDNal ^ -BK): k (415) «0.32

95. Arg-Pro-Pro-Gly-Thi-Ser-CDF-Thi-Arg (Thi ^ gCDF ^ -BK): k (415) «0.28

96. Arg-Pro-Pro-Gly-Thi-Ser-DTyr-Thi-Arg (Thi ^ gDTyr ^ -BK) s k (415) »0.12

97. Arg-Pro-Pro-Gly-Thi-Ser-DVal-Thi-Arg (Th ± ₅ gDVal ^ -BK): k (415) «0.11

98. Arg-Pro-Pro-Gly-Thi-Ser-DIle-Thi-Arg (Th ± ₅ gDIle ^ -BK); k (415) 0.16

99. Arg-Pro-Pro-Gly-Thi-Ser-DLeu-Thi-Arg (Thi ^ gDLeu ^ -BK)

100. Arg-Pro-Pro-Gly-Thi-Ser-DTrp-Thi-Arg (Th ± ₅ gDTrp ^ -BK)

101. Arg-Pro-Pro-Gly-Thi-Ser-DPhg-Thi-Arg (Thi ^ gDPhg ^ -BK)

102. Arg-Pro-Pro-Gly-Thi-Ser-DHis-Thl-Arg (Thi ^ gDHis ^ -BK)

103. Arg-Pro-Pro-Gly-Thi-Ser-DOMT-Thi-Arg (Th ± ₅ gDOMT ^ -BK): k (415) = 0.18

EXAMPLES OF THE ACTIVITY OF BRADIQUININE ANTAGONISTS

According to the commonly accepted methods for testing bradykinin and related quinines, as described by Trautschold (Handbook of Expt. Pharmacol. Vol. 25, Springer Verlag, pages 53-55, 1970) in relation to inhibiting the myotropic action of bradykinin, antagonis /

of this compound in natural or rat-induced uterus and in guinea pig ileum. Inhibition capacities in rat uterus (RUT) and guinea pig ileum (GPl) were determined, as described by Schild in relation to antagonists of biologically active compounds (Br. J. Pharmacol. 2; I89, 1947), using commonly accepted methods. In these tests, the dose-response curve for the reference substance, bradykinin is determined. The dose of bradykinin that pro-

maximum contraction

The tissue is administered 30 seconds before the start of its incubation with a dose of antagonist an amount of bradykinin equivalent to twice the dose DE__

In this protocol, the doses of the antagonist are increased until pre-incubation with a dose of the same reduces the contraction caused by the double dose

DE _t - bradykinin until a reaction equal to that produced by a single dose of bradykinin is achieved. The pA _o value represents the negative logarithm of the molar concentration of antagonists needed to reduce the response of a double DE ^ dose of bradykinin to that of a ΒΕ ^ θ dose. A unit of the pA value _o represents a situation of magnitude change in the capacity. Similarly, the negative logarithm of the dose of bradykinin it causes. 5θ% of the maximum contraction of the tissues is currently known as the pD ₉ value. Bradykinin has a value of 7.9 when _the .beta. acts on the rat uterus and 7.4 quan acts on the guinea pig ileum.

POWER OF BRADIQUININE ANTAGONISTS

EXAMPLE # pA2 / RUT STRUCTURE

DPhe ^ -BK pA2 / GPI

5.0

2 DThi ^ -BK 4.6 3 DPal ^ -BK 5.0 4.8 4 DPhe, - _-BK °, í 5.2 5 DPhe ₆ CDF ₇ -BK 4.9 5.8 6 Thi_ _Q DPhe_-BK 5.0 7 6.5 6.3 7 Thi_ _to DThi_-BK 5, the 7 4.2 5.8 8 Thi _{K to} DPal_-BK 5, the 7 4.2 10 DArg ₀ -DPhe _? -BK 5.6 11 DArg _Q -DPro ₃ DPhe ₇ -BK 4.0 13 Lys-Lys-DPhe ₇ -BK 5.1 14 Lys-Lys-Thi ^ gDPhe ₇ ~ BK 6.0 5.3 15 DArg ₀ -Th ± _{5 g} DPhe ₇ -BK 5.5 6.1 16 DArg -DPro „Thi · _Q DPhe„ -BK 0 j 5,0 7 5.2 18 Hyp ₂ Thi ₅ gDPhe ^ BK 5.6 19 Lys-Lys-Hyp ₂ Thi ₅ gDPhe ^ BK 5.8 20 Hyp ^ Thi ^ gDPhe ^ BK 7.0 4.7 21 DArgQ-Hyp ^ Thi ^ gDPhe ^ BK 7.2 22 Hyp _{2 3} Th ± ₅ gDPhe ^ BK 6.7 23 Hyp _{2 3} Th ± _{5 g} DPhe ₆ CDF ₇ -BK 6.5 64 DArg ₀ -Hyp ₂ Thi ₅ gDPhe ^ BK 5.7 65 DAr _{g ()} -Hyp ₂ , ₃ Thi ₅ , gDPhe ₇ -BK 7.1 72 Lys-Lys-Hyp ₂ DPhe ₇ -BK 5.6 77 Lys-Lys-Hyp ₃ Thi ₅ gDPhe ^ BK 6.7

EXAMPLE OF THE SPECIFICITY OF ANTAGONISM IN THE SMOOTH MUSCLE IN RELATION TO QUININAS

The specificity of bradykinin antagonists according to the present invention is demonstrated by the ability they exhibit to inhibit the myotropic activity of bradl-35 f quinine (BK) and two kinins related to the first and important from the point of view physiological, kallidin (KAL, Lys-BK) and methionyl-lysyl-BK (MK-BK), but not the myotropic activity induced by the quinine-related peptides such as angiotensin II (ANG) or substance P (SP). In each of these cases, as shown, bradykinin-related antagonists inhibit the contractions produced by the related agonists but have no effect on myotropic peptide substances not related to quinine. The inhibition capacities shown in the following table are called pAg * values

Evaluation of the Specificity of bradykinin antagonists in guinea pig ileum

EXAMPLE # STRUCTURE OF GUINEA PIG

BK KAL MK-BK ANG SP 1 DPhe ^ -BK 5.0 5.6 6.0 No No 6 Thi_ _Q DPhe -BK 5, the 6.3 6.4 5.2 No No 10 DArg _Q -DPhe ^ -BK 5.6 6.0 6.3 No No 15 DArg _rt -Thi _{c Q} DPhe_-BK O 5.0 ( 6.1 6.7 6.4 No No

EXAMPLE OF ANTAGONISM EXERCISED BY BRADIQUININE ANTAGONISTS ON BLOOD PRESSURE IN RAT

According to the tests described by Roblero,

Ryan and Stewart (Res, Commun, Pathol. Pharmacol. 6s2O7, 1973), evaluated the effects of the antagonists of bradykinl36 in in vivo.

blood pressure in the anesthetized rat. When if

25 jug / min, the response is reduced to a low dose.

minutes after completing the administration of the antagonist the depressant effect of bradykinin returns to a normal response. These antagonists also produce inhibition of the response to bradykinin when injected in the form of a concentrated mixture of bradykinin and antagonists, either via the intraaortic route or the intravenous route.

EXAMPLES OF APPEARANCE OF RESISTANCE TO ENZYMATIC DEGRADATION BY INCREASING EXTREMITY

N-TERMINAL OF BRADIQUININE ANALOGS.

The ability of bradykinin analogs to resist enzymatic degradation, in vivo, caused by, for example, kininases, can be conveniently evaluated, determining, for example, the residual vasodepressor action of a given analogue after a single passage in the pulmonary circulation in the rat anesthetized (j. Roblero, JW Ryan and JM Stewart, Res. Commun. Pathol. Pharmacol. 6: 207, 1973) after administered intravenously and intravenously. In this system and using N-terminal substituted bradykinin analogs (agonists) the following results are obtained:

.- 37

PULMONARY DESTRUCTION IN THE RAT OF ANALOGUE

BRADIQUININ MODIFIED AT N-TERMINAL END

PEPTIDIC STRUCTURE $ DESTRUCTION

Bradykinin (BK)

Lys-BK95

DArg-BK92

DLys-BK89

Lys-Lys-BK

Thi_ _q -BK

5, »

Lys-Lys-Thl ^ g-BK

The resistance of the increased bradykinin analogs at the N-terminal end to kinase degradation, especially those exhibiting Lys-Lys elongations, suggests that bradykinin activity antagonists that act for a long time by modifying / D-Phe ^ inhibitors can be obtained. __7-BK with a Lys-Lys stretch. Furthermore, it has been observed that the addition of a remainder of D-Arg to the

agonists

source

uterine potency without affecting the ileum activity, synthesis of D-Phe ^ -BK analogs increased with a D-Arg remainder which act as specific tissue inhibitors.

elongation of the N-terminal end of the

- 3 8

D-Phey-BK with Lys-Lys or with the residue of D-Arg reduced the agonist capacity in the uterine assay but had no effect on the antagonism observed in the ileum assay. In a similar way, the inhibitory action of Thi ^ g-DPhe was reduced

-BK over the uterus by adding either a Lys-Lys stretch or a D-Arg rest to the N-terminal end. In the ileum test, the addition of a remainder of D-Arg to the Thi ^ g-DPhey-BK antagonist, which is very potent, produced only a slight action on the inhibitory potency.

EXAMPLES OF APPEARANCE OF TISSUE SELECTIVITY MODIFYING BRADIQUININE ANTAGONISTS IN POSITIONS

E 3

Bradykinin agonists prepared by modifying the bradykinin nonapeptide sequence exhibit, in the classic assays in rat uterus (RUT) and guinea pig ileum (GPl), similar capabilities to bradykinin. Recently, the dissociation of smooth muscle activities has been described by bradykinin analogs containing aminoisobutyric acid (Aib) at position 7 (R. J · Vavrek and JM Stewart, Peptides 1: 231, 1980) and by bradykinin analogs with multiple substitutions by amino acids with the D configuration in positions 6 and 7 (RJ Vavrek and JM Stewart, in Kinins 1984, LM Greenbaum, cd., Plenum Press, NY, 1985) with respect to significantly intense uterine activity vs ileum activity.

The addition of a D-shaped amino acid remainder, such as D-Arg, to the N-terminal end of

a bradykinin antagonist, selective for the ileum, such as

DPhey-BK, which results in DArg ^ -DPhey-BK, does not alter the selectivity in relation to the inhibitory activity of bradykinin on this organ. Modifying DPhey-BK in position 3 by adding a remainder of DPro resulting in DProj-DPhey-BK eliminates antagonist activity in the ileum assay and destroys agonist activity in the uterine assay. The substitution of the rest of Pro in position 3 in DArgQ-DPhey-BK reverses the spectrum of smooth muscle activity in relation to selective antagonism in the uterus, with total loss of bradykinin antagonism in the ileum. Likewise, the replacement of a remainder of Pro in position 3 in the non-specific DArg _Q -Thi ^ _g -DPheyresto antagonist of DPro eliminates the antagonism to the action of bra-BK by the diquinin in the ileum, but the antagonistic action in the uterine assay remains total

ANTAGONIST SPECIFICITY IN MUSCLE TESTS

SMOOTH WITH MODIFICATION OF POSITION 3

EXAMPLE # STRUCTURE RUT GPI 1 DPhey-BK (1 $ AG) pA ₂ = 5.0 10 DArδθ-DPhey-BK (0.1 $ AG) pA ₂ = 5.0 59 DPro ^ -DPhey-BK 0 0 11 DArg ₀ -DPro3-DPhey-BK pAg = 4.6 0 15 DArg _Q -Thi ₅ gDPhey-BK pA ₂ = 5.2 pA ₂ = 6.1 16 DArg ₀ -DPro ^ Thi ^ _g - DPhey-BK P-Ag ⁼ 5.2 0

- 4ο AG «agonist capacity in relation to 100 parts of bradykinin, pAg is the capacity of inhibition according to the definition of Schild (Br, J, Pharmacol. 2: 189, 1947).

It is also possible to alter the tissue selectivity of bradykinin analogues by modifying the rest of Pro in position 2, It was observed that the substitutions made with Vai, Sar, Pro, Ala, Hyp and Aib -aminoisobutirato) in position 2 confer a different tissue selectivity of the bradykinin analogs used in the assay of myotropic activity evaluated in guinea pig ileus versus rat uterus (RJ Vavrek and J, M, Stewart, Peptides, 231-235, 1980), The tissue selectivity that these substitutions in position 2 confer several bradykinin analogs suggest that a similar substitution in any bradykinin analogue, including those that exhibit antagonistic activity, confers tissue selectivity.

Therapeutic applications of the new bradykinin antagonists include treatment related not only to the production by the animal itself of bradykinin or related quinines, but also to the injection of peptj into the animal. related to bradykinin as a consequence of hard bites and stings. Topical application may be used individually or in combination with a subcutaneous administration of bradykinin antagonists according to the present invention, to treat the effects of bradykinin-related peptides such as pain, inflammation and swelling.

Can be used therapeutically successfully,

bradykinin tagonists according to the present invention in other traumatic, inflammatory or pathological situations that are known to suffer the intervention of bradykinin or to be exacerbated by its overproduction. These conditions include local injuries such as wounds, burns and rashes, angina, arthritis, asthma, allergies, rhinitis, shock, stomach inflammations, low blood pressure, systemic treatment of pain and inflammation and reduced sperm motility that causes sterility male. As mentioned, bradykinin antagonists according to the present invention can be advantageously administered through various routes of administration including sublingual absorption such as nitroglycerin or through transdermal therapeutic systems using agents that favor absorption through of the skin as used in the treatment of angina.

Based on the PAg and DE_ _rt values according to the present invention and the scientific work already carried out and related to the agonist capacity, it is possible for experts in the field to calculate the dose of the new bradykinin agonists according to the present invention.

Consequently, it was assessed that the characteristic dose administered in situations of pain and inflammation of wounds, burns and rashes should be between 0.1 and 5 mg / ml; in spray presentations ”for nasal administration and appropriate for the treatment of rhinitis, allergies and asthma the appropriate dose should be between 0.1 and 5 mg / ml; in presentations to be administered intravenously and appropriate for the treatment of systemic inflammation, shock, arthritis, allergies and asthma and to increase the

sperm motility the appropriate dose should be between 0.1 and 10 mg / kg; in presentations for oral administration and appropriate for the treatment of stomach inflammation or pain and general inflammation the appropriate dose should be between 10 and 100 mg / kg. Bradykinin antagonists can also be administered through the vagina, rectum, mouth or through another acceptable internal route.

As those skilled in the art recognize, the present invention has a wide area of application providing inhibitors competitive with the biological activities of bradykinin produced by the injured, traumatized and shocked organism. The advantages of the present invention in replacing L-Pro in position 7 by amino acids with the D configuration, to convert bradykinin agonists into antagonists are to provide a wide variety of specific and competitive antagonists that reduce the known effects of bradykinin. The additional advantages according to the present invention, modifying the 7-position of the L-Pro in conjunction with modifications in other positions of the new antagonists are to provide a variety of useful compounds. It can also be seen that the present invention is susceptible to these and other modifications within its parameters without departing from the scope of its claims.

Claims (26)

1, - Process for the preparation of peptides derived from bradykinin of general formula A-Arg-B-C-D-W-X-Y-Z-Arg I in which A represents a hydrogen atom, a remainder of amino acids with the D or L configuration, a dipeptide containing amino acids with the D or L configuration, a polypeptide comprising amino acids with the D or L configuration, a group terminal nitrogen protecting type of acyl type, aromatic urethane or an alkyl type protecting group; B represents a group D or L-proline (Pro), D or L-cyclic aliphatic amino acid, D or L-aliphatic amino acid, D or L-aromatic amino acid or D or substituted aromatic L-amino acid ; C represents a group D-proline (Pro), L-proline (Pro), D or L-cyclic amino acid, D or L aliphatic amino acid, D or L-aromatic amino acid or D or L- substituted aromatic amino acid; D represents a glycine (Gly) group, aliphatic L-amino acid, aromatic L-amino acid or substituted aromatic L-amino acid; W represents a substituted L-phenylalanine (Phe), L-phenylalanine (Phe), aliphatic L-amino acid, aromatic L-amino acid or L-amino group - substituted aromatic acid; X represents a group L-serine (Ser), glycine (Gly), D or L-amino acid aliphatic, D or L-amino acid aromatic or D or L-amino acid aromatic substituted; Y represents an aromatic D-amino acid, substituted aromatic D-amino acid or aliphatic D-amino acid group; and Z represents a group L-phenylalanine (Phe), substituted L-phenylalanine, aliphatic L-amino acid, aromatic L-amino acid or substituted aromatic L-amino acid; and its pharmaceutically acceptable salts, characterized by the fact that an L-proline group in position 7 is substituted with amino acids of configuration D, to obtain compounds with antagonistic activity of bradykinin, to reinforce this action and to confer enzyme resistance and / or tissue specificity through additional substitutions in other positions. 2 - Process according to claim 1, for the preparation of compounds of general formula I, in which the symbol Y represents DPhe, beta-2-thienyl-DAla (DThi), beta-2-pyridyl-DAla (DPal), beta-2-naphthyl-DAla (DNal), DHis, D-homo-Phe (DhPhe), O-methyl- DTyr (DOMT), D-alpha-phenyl-Gly (DPhg), DTrp, DTyr, pN0 ₂ -DPhe (PNF) or pCl-DPhe (CDF), characterized by the fact that starting from the correspondingly substituted starting compounds, Process according to claim 1 or 2, for the preparation of compounds of general formula I with the following sequence Arg-Arg-Pro-Pro-Gly-Phe-S er-Y-Phe-Arg and its pharmaceutically acceptable salts, characterized by the fact that correspondingly substituted starting compounds are used. 4. A process according to claim 3 for the preparation of compounds of the general formula I in which the Y symbol represents a D-phenylalanine group (DPhe) and its pharmaceutically acceptable salts, characterized by the fact that use correspondingly substituted starting compounds. 5. A process according to claim 1 or 2 for the preparation of compounds of general formula I in which Y represents a remainder of a simple D-amino acid, W represents an amino acid comprising a thienyl group and Z represents an amino acid containing a thienyl group, and its pharmaceutically acceptable salts, characterized by the use of correspondingly substituted starting compounds. A process according to claim 1 for the preparation of compounds of general formula I in which: a, the symbol A represents an atom or group chosen from: i) a hydrogen atom, ii) a remainder of an amino acid with the configuration D or L, iii) an N-terminal protecting group, - Ιι6 iv) a dipeptide, and v) a polypeptide: B. B represents one rest in one L-amino acid; ç. Ç represents one rest in one amino acid; d. D represents one rest in one L-amino acid; and. W represents one rest in one amino acid; f. X represents one rest in one amino acid; g. Y represents one rest in one D-aromatic amino acid · typical; and H. Z represents one rest in one amino acid, and its pharmaceutically acceptable salts, characterized in that color-substituted starting compounds are used. 7. A process according to claim 6 for the preparation of compounds of general formula I in which: A represents a group chosen from D-Arg, D-Lys, L-Thi, Lys-Lys, Met-Lys and Gly-Arg-Met-Lys; B represents a group chosen from L-Pro, L-hydroxyproline, aminoisobutyric acid (Aib), L-azetidine-2-carboxylic acid (Azt), L-thiazolidine-2-carboxylic acid (Thz), isonipecotic acid (inip) and L-dehydroproline; C represents a D- or L-proline (Pro) group; D represents a glycine (Gly) or L-alanine (L-Ala) group; W represents a group chosen from L-phenylalanine (L-Phe) or substituted phenylalanine, leucine (Leu), beta-2-thienylalanine (Thi), beta-2-naphthylalinine (Nal), 2- -pyridyl-alanine (Pal) and O-methyl-tyrosine (OMT); X represents a group chosen from L-serine (Ser), glycine (Gly), p-chloro-D-phenylalanine (pCl-DPhe) or D-phenylalanine (D-Phe); Y represents a group chosen from D-phenylalanine (D-Phe), beta-2-thienyl-D-alanine (D-Thi), beta-2-pyridyl-D-alanine, beta-2-naphthyl-D-alanine, D-histidine (D-His), D-homo-phenylalanine, ortho-methyl-D-tyrosine (DOMT), D-alpha-phenyl-glycine (DPhg), D-tryptophan (DTrp), D-tyrosine (D- Tyr) and para-chloro-D-phenylalanine (CDF); and Z represents a group chosen from Leu, Thi, Pal, Phe, or substituted Phe, Thi, O-methyl-Tyr (OMT) or beta-2-naphthyl-Ala- (Nal), characterized by the fact that initial compounds are used correspondingly replaced. 8. A process according to claim 6 for the preparation of compounds of the general formula I in which A represents a hydrogen atom, B represents a Pro group, C represents a Pro group, D represents a Gly group, X repr a Ser group, W represents a Phe group and Z represents a Phe group, characterized by the fact that correspondingly substituted starting compounds are used. 9. Process according to claim 6 for the preparation of compounds of general formula I, in which the symbol Y represents DPhe, beta-2-thienyl-DAla, (DThi), beta-2-pyridyl-DAla (DPal), 2-naphthyl-DAla (DNal), DHis, D-homo- -Phe (DhPhe), O-methyl-DTyr (DOMT), D-alpha-phenyl-Gly (DPhg), DTrp, DTyr or pCl-DPhe (CDF), characterized by the use of correspondingly substituted initial compounds. 10. A process according to claim 6 for the preparation of compounds of the general formula I in which Y has a simple D-amino acid, W represents a remainder of an amino acid containing a thienyl group and Z represents an amino acid comprising a thienyl group and its pharmaceutically acceptable salts, characterized in that correspondingly substituted starting compounds are used, Process according to any one of claims 6, 9 or 10, for the preparation of compounds of the general formula I in which the symbol B represents hydroxyproline and / or the symbol C represents hydroxyproline, characterized in that initial compounds are used correspondingly replaced. 12. The process of claim 1 for preparing modified antagonist peptides of general formula (Arg-B-C-D-W-X-Y-Z-Arg) I in which A represents arginine; B represents L-Pro, a cyclic aliphatic L-amino acid, an aliphatic L-amino acid, a aromatic L-amino acid or a substituted aromatic L-amino acid; C represents a D-Pro group, an L-Pro group, an amino- -cyclic acid, an aliphatic amino acid, an aromatic amino acid or an aromatic amino acid substituted with the D configuration; D represents a Gly group, an aliphatic amino acid, an aromatic amino acid or an aromatic amino acid substituted with the L configuration; W represents an L-Phe or substituted Phe group, an aliphatic amino acid or aromatic amino acid; X represents an L-Ser group, a Gly group, an aliphatic D- or L-amino acid, an aromatic D- or L-amino acid or a substituted aromatic D- or L-amino acid; Y represents an aromatic D-amino acid or a substituted aromatic D-amino acid; and Z represents an L-Phe or substituted Phe group, an aliphatic amino acid or an aromatic amino acid; and its pharmaceutically acceptable salts, characterized by the fact that correspondingly substituted starting compounds are used. 13.- The process of claim 12 for the preparation of modified antagonist peptides of general formula I in which the symbol Y represents: (DPhe), beta-2-thienyl-DAla (DThi), beta-2-pyridyl-DAla (DPal), beta-2-naphthyl-DAla (D-Nal), DHis, D-homo-Phe (DhPhe), O-methyl-DTyr (DOMT), D-alpha-phenyl-Gly (DPhg), DTrp, DTyr or pCl-DPhe (CDF); and its pharmaceutically acceptable salts, characterized by the use of starting compounds - 50 respondents replaced. 14. A process according to claim 12 or 13 for the preparation of modified antagonistic peptide compounds of general formula (Arg-Pro-Pro-Gly-Phe-Ser-Y-Phe-Arg) and their acceptable salts in pharmacy, characterized by the fact that correspondingly substituted starting compounds are used, 15. A process according to claim 14 for the preparation of the modified antagonist peptide compounds referred to therein, in which the general formula Y represents a D-Phe group and its pharmaceutically acceptable salts, characterized in that initial compounds are used. color responsively replaced, 16. A process according to claim 12 or 13 for the preparation of peptide antagonist compounds modified with the general formula mentioned therein in which Y represents a simple D-amino acid and W and Z represent, each, an amino acid comprising a thienyl group, or its pharmaceutically acceptable salts, characterized by the use of correspondingly substituted starting compounds. 17. A process according to claim 12 or 13 for the preparation of antagonist peptide compounds modified with the general formula defined therein, in which the symbol B represents L-hydroxyproline, D represents alanine (Ala), W represents leucine (Leu), beta-2-thienyl-alanine (Thi) or 2-pyridyl-alanine (PaL), X stands for chloro-D-phenylalanine (pCl-D-Phe) or D-Phe and Z represents Leu , Thi or Pal, characterized by the fact that correspondingly substituted starting compounds are used * 18. A process according to claim 12 or 13 for the preparation of compounds with the general formula defined therein, in which the symbols B and C each represent hydroxyproline, W represents beta-2-thienyl- alanine (Thi), Y represents an aromatic substituted D-amino acid and Z represents beta-2-thienylalanine (Thi), characterized by the fact that initial compounds are used which are substituted. 19 - Process for the preparation of pharmaceutical compositions, characterized in that a therapeutically effective amount of a compound of formula I, prepared by the process according to any one of claims 1 or 2, is combined which has enhanced resistance to enzymatic degradation and wherein the symbol A represents D-Arg, D-Lys, Lys-Lys, L-Thi, Met-Lys or Gly-Arg-Met-Lys or their pharmaceutically acceptable salts, as an ingredient active, with a pharmacy-acceptable vehicle. 20, - Process for the preparation of pharmaceutical compositions, characterized in that a therapeutically effective amount of a compound of formula I, prepared by the process according to claim 1 or 2, is combined, which has enhanced tissue selectivity and in which the symbols A and / or C represent groups chosen from L-Pro, L-hydroxyproline, D-Pro, D-valine, L-valine, alpha-aminoisobutyric acid (Aib), L-Ala, D-Ala, Sar, D- Gly, L-Gly and its pharmaceutically acceptable salts, as an active ingredient, with a pharmaceutically acceptable carrier. 21. Process for the preparation of pharmaceutical compositions, characterized in that an effective amount of a compound of general formula I is prepared, prepared by the process according to any one of claims 1 or 2, which has enhanced potency, and in which the symbols V and / or Z represent groups chosen among Phe, O-methyl-Tyr (OMT), p-chloro-Phe (CLF), p-nitro-Phe (PNF), beta-2-naphthyl-Ala (NAL), Tyr, Thi and Pal, and their salts pharmaceutically acceptable as an active ingredient with a pharmaceutically acceptable carrier. 22. Process for the preparation of pharmaceutical compositions, characterized in that a therapeutically effective amount of a compound prepared by the process according to any of claims 6 or 9 is combined, which has enhanced resistance to enzymatic degradation, wherein the symbol A represents a D-Arg, D-Lys, Lys-Lys, Met-Lys or Gly-Arg-Met-Lys group or their pharmaceutically acceptable salts as an active ingredient, with a pharmaceutically acceptable carrier. 23. Process for the preparation of pharmaceutical compositions, characterized in that a therapeutically effective amount of a compound prepared by the process according to one of claims 6 or 9 is combined, which has enhanced tissue selectivity and in which the symptoms cakes B and / or C each represent a group chosen from L-Pro, L-hydroxyproline, D-Pro, -Pro, D-valine, L-valine, alpha-aminoisobutyric acid (Aib), L-Ala, D-Ala, Sar, D-Gly or L-Gly and their pharmaceutically acceptable salts, as an active ingredient, with a pharmaceutically acceptable carrier. 24. Process for the preparation of pharmaceutical compositions, characterized in that a therapeutically effective amount of a compound prepared by the process according to any one of the claims is combined 6 or 9, which has enhanced power and where the symbols W and / or Z represent groups chosen from Phe, Thi, Tyr, Pal, O-methyl-Tyr (OMT), para-chloro-Phe (CLF), para- nitro-Phe (PNF) and Beta-2-naphthyl-Ala (Nal), and their pharmaceutically acceptable salts, as an active ingredient, with a pharmaceutically acceptable carrier. 25. Process for the preparation of pharmaceutical compositions, characterized in that a therapeutically effective amount of a modified antagonist peptide prepared by the process according to any one of claims 12 or 13, which has enhanced tissue selectivity and in which the symbols are combined B and / or C represent groups chosen from L-Pro, L-hydroxyproline, D-Pro or D-Pro, D-valine, L-valine, alpha-aminoisobutyric acid (Acb), L-Ala D-Ala, Sar, D-Gly or L-Gly, and their pharmaceutically acceptable salts, as an active ingredient, with a pharmaceutically acceptable carrier. 26. Process for the preparation of pharmaceutical compositions, characterized in that a therapeutically effective amount of a modified antagonist peptide prepared by the process according to any one of claims 12 or 13 is combined, which has enhanced potency and in which the symbols W and / or Z represent groups chosen from Thi, Pal, Nal, OMT, PNF, CLF, and their pharmaceutically acceptable salts, as an active ingredient, with a pharmaceutically acceptable carrier.