MXPA97002292A - Use of bradiquinine antagonists for the preparation of medicines intended for the treatment of chronic fibrogenetic hepatic diseases and hepatic diseases agu - Google Patents

Abstract

The invention relates to the use of bradykinin antagonists for the preparation of medicaments for the treatment of chronic fibrogenetic liver diseases (liver cirrhosis and liver fibrosis) and water liver diseases and for the prevention of complications, especially for the prophylaxis or treatment of hypertonia. portal, decompensation phenomena such as ascites, edema formation, hepatorenal syndrome, hypertensive gastropathy and colopathy, splenomegaly as well as complications due to hemorrhages in the gastrointestinal tract of portal hypertonia, collateral circulation and hyperemia, and heart disease as a consequence of a chronic hyperdynamic circulatory situation and its sequels

Description

Use of bradykinin antagonists for the preparation of drugs for the treatment of chronic fibrogenetic liver diseases and acute liver diseases The invention relates to the use of bradykinin antagonists for the preparation of medicaments for the treatment of chronic fibrogenetic liver diseases (hepatic cirrhosis and liver fibrosis) as well as acute liver diseases, and for the prevention of complications. Bradykinin and the related peptides are powerful inflammation and pain-generating substances as well as vasoactive, typical of the body. It is known to use bradykinin antagonists as agents to combat conditions that are mediated, provoked or sustained by bradykinin (European patent document EP-B-0,370,453). Surprisingly, it was finally discovered that bradykinin antagonists are suitable agents for the treatment of chronic fibrogenetic liver diseases (liver cirrhosis and hepatic fibrosis) and acute liver diseases, as well as for the prevention of complications, especially for the prophylaxis or treatment of portal hypertonia, decompensation phenomena such as ascites, edema formation, hepatorenal syndrome, gastropathy and hypertensive colopathy, splenomegaly as well as complications from gastrointestinal tract hemorrhages due to portal hypertonia, collateral circulation and hyperemia, as well as cardiopathy as a consequence of a chronic iperdynamic circulatory situation, and its sequelae. As compounds, bradykinin antagonists, which exhibit a natriuretic effect in the model of hepatic fibrosis induced by CC14 in a rat, are suitable. Particularly suitable antagonists of bradykinin are, inter alia, the peptides of the formula I Z-P-A-B-C-E-F-K- < D) Q - G - M - F '- I (I), in which they mean: Z a- ^ hydrogen, alkyl (C ^ Cg), alkanoyl (C ^ Cg), alkoxy (Cj ^ C) -carbonyl, cycloalkyl (C3-C8), cycloalkanoyl (C4-C8) or alkyl (C1-Cg) -sulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or 3 radicals, equal or different, taken from the series consisting of carboxy, NHR (l), [(C1-C4) alkyl] NR (1) or [aryl (C6-C1 (J) -alkyl (C ^ -C ^)] NR (1) ), where R (l) represents hydrogen or a protecting group of urethane, (C1-C4) alkyl, (C1-C8) alkyl-amino, aryl (Cg-C10) -alkyl (C - ^ - C, ^) -amino , hydroxy, alkoxy, halogen, di- [(C1-C8) alkyl] -no, di- [aryl (Cg-C1Q) -alkyl (C1-C4) -amino, carbamoyl, phthalimido, 1,8-naphimidate , sulfamoyl, alkoxy (C - ^ - C ^ j) -carbonyl, aryl (Cg-C14) and aryl (Cg-C14) -alkyl (C ^ Cg), or in which in each case 1 hydrogen atom is eventually replaced by a radical taken from the series formed by cycloalk ilo (C3-C8), alkyl (C1-C8) -sulfonyl, alkyl (C- | _-Cg) -sulfinyl, aryl (Cg-C14) -alkyl (C1-C4) -sulfonyl, aryl (Cg-C14) -alkyl (C1-C4) -sulfinyl, aryl (Cg-C14), aryloxy (C8-C14), heteroaryl (C3-C13) and heteroaryloxy (C3-C13) and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals taken from the series consisting of carboxy, amino, alkyl (C ^ C) -amino, hydroxy, alkoxy (CL-C4), halogen, di- [alkyl (C ^ Cg)] -amino, carbamoyl, sulfamoyl , (C1-C4) alkoxycarbonyl, aryl (Cg-C14) and aryl (Cg-C14) -alkyl (C1-C5); a2) aryl (Cg-C14), aroyl (C7-C15), aryl (Cg-C14) -sulfonyl, heteroaryl (C3-C13) or heteroaroyl (C3-C13); a3) carbamoyl, which may optionally be substituted on the nitrogen with (C - ^ - Cg) alkyl, (Cg - C14) aryl or (Cg - C14) aryl - (C1 - C5) alkyl; it being realized, in the radicals defined in sections a- ^), a2) and a3), that the aryl, heteroaryl, aroyl, arylsulfonyl and heteroaroyl groups are optionally substituted with 1, 2, 3 or 4 radicals taken from the series formed by carboxy, amino, nitro, alkyl (C - ^ - Cg) -amino, hydroxy, alkyl (C - ^ - Cg), alkoxy (C - ^ - Cg), aryl (Cg-C14), aroyl (C7-C15) , halogen, cyano, di- [(C 1 -C 8) alkyl] -amino, carbamoyl, sulfamoyl, and (C 1 -C 4) alkoxycarbonyl; P a direct link or a radical of formula II, - NR (2) - (U) - CO - (ID wherein R (2) means hydrogen, methyl or a urethane protecting group, U means (C3-C8) cycloalkylidene, arylidene (Cg-C14) heteroarylidene (C3-C13), aryl (Cg-C14) -alkylidene (C) ^ -Cg), which may be optionally substituted, or [CHR (3)] n, where n 1-8, preferably 1-6, meaning R (3), independently of one another, hydrogen, alkyl (Cj ^ -Cg), cycloalkyl (C3-C8), aryl (Cg-C14), heteroaryl (C3-C13), which, with the exception of hydrogen, are in each case possibly monosubstituted with amino, substituted amino, amidino, substituted amidino, hydroxy, carboxy, carbamoyl, guanidino, substituted guanidino, ureido, substituted ureido, mercapto, methylmercap or, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 1,8-naphthalimido , 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, preferably representing the amino-N (A ') -Z, the amidino preferably substituted - (H =) C-NH-Z, the guanidino preferably substituted -N (A ') -C [= N (A #)] -NH-Z and the ureido substituted preferably -C0-N (A ') - Z, in which the A', independently of each other, mean hydrogen or Z, where Z is defined as in a-^ or a2); or in which R (2) and R (3), in common with the atoms that carry them, form a monocyclic, bicyclic or tricyclic ring system with 2 to 15 carbon atoms, -A as defined P; B a basic amino acid in the L or D configuration, which may be substituted in the side chain; C a compound of the formula Illa or IIIb G'-G'-Gly G'-NH- (CH2) p-C0 (III a) (III b) wherein p is from 2 to 8, and the 6 ', independently of each other, mean a radical of formula IV -NR (4) -CHR (5) -CO- (| V) wherein R (4) and R (5), in common with the atoms that carry it, form a monocyclic, bicyclic or tricyclic, heterocyclic ring system with 2 to 15 C atoms; E the radical of an aliphatic or alicyclic-aliphatic, neutral, acid or basic amino acid, -F, independently of each other, the radical of an aliphatic or aromatic, neutral, acidic or basic amino acid, which may be substituted in the chain lateral, or a direct bond, - (D) Q D-Tic, D-Phe, D-Oic, D-Thi or D-Nal, which may eventually be substituted with halogen, methyl or methoxy, or a radical of the following formula (V) wherein X represents oxygen, sulfur or a direct bond, - R means hydrogen, alkyl (C - ^ - Cg), cycloalkyl (C3-C8), aryl (Cg-C14), aryl (Cg-C14) -alkyl ( C1-C4), the alicyclic radical being optionally substituted with halogen, methyl or methoxy; G as defined G 'before or a direct link; F 'as defined F, a radical NH-ICE ^), -.-, where q = from 2 to 8, or, in the case where G does not mean any direct bond, a direct bond; I -OH, -NH2 or -NHC2H5; K the radical -NH- (CH2)? -CO-, in? Pae x = 1-4 or a direct bond, and M as defined F, as well as their physiologically compatible salts. Suitable bradykinin antagonists are described, for example, in patent applications WO 95/07294 [Scios Nova, pseudopeptides], WO 94/08607 [Scios Nova, pseudopeptides], WO 94/06453 [Stewart, aliphatic amino acid in position 5], WO 93/11789 [Nova], EP-A-552,106 [Adir], EP-A-578,521 [Adir], WO 94/19372 [Scios Nova, Cyclo-Peptides], EP-A-370.453 [Hoec st], EP-A-472,220 [Syntex], WO 92/18155 [Nova], WO 92/18156 [Nova], WO 92/17201 [Cortech] and WO 94/11021 [Cortech; bradykinin antagonists of formula X (BKA) n wherein X is a linking member, BKA is the peptide chain of an antagonist, bradykinin and n is an integer greater than 1, - bradykinin antagonists of formula X ( BKA); and bradykinin antagonists of the formula (Y) (X) (BKA) wherein Y is equal to a ligand, which is an antagonist or an agonist for a non-bradykinin receptor]. Particularly suitable are the peptides of the formula I, in which they mean: Z hydrogen or as defined above in a), a2) or a3), P a bond or a radical of the formula IINR (2) - (U) - CO - (II) where U is equal to CHR (3) and R (3) is as before defined, R (2) is equal to H or CH3, and A a link. Especially preferred are compounds of formula I, in which they mean: Z hydrogen or as defined above in a), a2) or a3), P a bond or a radical of formula II NR (2) - (U) - CO - (||) in which U is equal to CHR (3) and R (3), independently of one another, mean hydrogen, (C1-Cg) alkyl, cycloalkyl (C3) ~ Cg), aryl (C-C14), heteroaryl (C3-C13), which, with the exception of hydrogen, are in each case monosubstituted optionally with amino, substituted amino, hydroxy, carboxy, carbamoyl, guanidino, substituted guanidino, ureido , mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, -pyridyl or cyclohexyl, preferably representing the amino-N (A ') -Z and the guanidino preferably substituted -N (A') -C [= N (A ')] -NH-Z, in the that the A ', independently of one another, mean hydrogen or Z, where Z is defined as in a- ^) or a2); or in which R (2) and R (3), in common with the atoms that carry them, form a monocyclic, bicyclic or tricyclic ring system, with 2 to 15 C atoms, R (2) is equal to H or CH3, -A link; (D) Q D-Tic. Preferred are preferably: HD-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140) para-guani- dobenzoyl-Arg-Pro-Hyp-Gly-Th -Ser-DT¡c-0¡c-Arg-OH HD-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-HypE (transpropil) -0¡c-Arg-OH HD-Arg-Arg -Pro-Hyp-Gly-Cpg-Ser-D-Cpg-Cpg-Arg-OH HD-Arg-Arg-Pro-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH H-Arg (Cough) ) -Pro-Hyp-Gly-Thi-Ser-DTc-0c-Arg-OH H-Arg (Cough) -Pro-Hyp-Gly-Phe-Ser-DTc-Oic-Arg-OH HD -Arg-Arg-Pro-Hyp-Gly-Phe-Ser-DT-c-0¡c-Arg-OH Fmoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic- Arg-OH Fmoc-Aoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH Fmoc-e-amynocaproyl-D-Arg-Arg-Pro-Hyp- Gly-Thi-Ser-DTi'c-0'c-Arg-OH benzoyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH cyclohexylcarbonylD-Arg -Arg-Pro-Hyp-Gly-Thi-Ser-DTyc-Oic-Arg-OH Fmoc-Aeg (Fmoc) -D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DTi-C Oic-Arg-OH Fmoc-Aeg (Fmoc) -Arg-Pro-Hyp-Gly-Thi-Ser-DT-c-0¡c-Arg-OH ndol-3-N-acetyl-D-Arg-Arg- Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH dibenzylacetyl-D-Arg-Arg-Pro-Hyp-Gly-Thi- Ser-D-Tic-Oic-Arg-OH and its physiologically compatible salts. Especially suitable are HD-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140) para-guanidobenzoii-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic- Oic-Arg-OH and its physiologically compatible salts. H-D-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tc-0c-Arg-OH (HOE 140) and its physiologically compatible salts are very particularly suitable. The application can be made by the enteral, parenteral routes - such as p. ex. subcutaneous, intramuscular (i.m.) or intravenous (i.v.) -, nasal, recteile or by inhalation. The dosage of the active substance depends on body weight, age and mode of application. The pharmaceutical preparations of the present invention are produced according to known methods of dissolution, mixing, granulation, tabletting or dragee formation. For parenteral administration, the active compounds or their physiologically compatible salts, if desired together with the usual pharmaceutically acceptable excipients, for example for isotonization or pH adjustment, as well as solubilizers, emulsifiers or other adjuvants, are to the form of a solution, suspension or emulsion.

For the drugs described, the use of delayed injectable preparations is also appropriate for subcutaneous or intramuscular administration. As drug forms can be used p. ex. oily crystalline suspensions, microcapsules, microparticles, nanoparticles or implanted, the latter being able to be constituted based on polymers compatible with the tissues, especially biodegradable polymers, such as p. ex. based on copolymers of poly (lactic acid) -poly (glycolic acid). Other conceivable polymers are polyamides, polyesters, polyacetates or polysaccharides. For the oral application form, the active compounds are mixed with the usual additive materials for this, such as vehicle materials, stabilizers or inert diluents, and are brought by customary methods to appropriate forms of presentation and administration, such as tablets, dragees, nestable capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. As inert vehicles, p. ex. gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially corn starch. In this case, the preparation of solid drug forms can be carried out in the form of both a dry granulate and also a wet granulate. Suitable vegetable materials or oily solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil. Delayed preparations are also conceivable that have coatings resistant to gastric juices. Delayed preparations can be constituted based on fatty, waxy or polymeric embedments. In these cases, multilayer or coated tablets or granules are also possible. For the drugs described, an application on the mucous membranes is also opportune to achieve a systemically effective level. This concerns the possibility of application through the intranasal, inhalational and rectal routes. For the application form by intranasal route, the compounds are mixed with the usual additive materials for this, such as stabilizers or diluents and are carried by usual methods to appropriate forms of presentation and administration, such as powders, aqueous, alcoholic suspensions or oily, or aqueous solutions, alcoholic or oily. To the aqueous intranasal preparations, chelating compounds, such as ethylenediamine-N, N, N ', N' -tetraacetic acid and buffers such as acetic acid, phosphoric acid, citric acid, tartaric acid and their salts can be added. The multi-dose containers contain preservative agents such as benzalkonium chloride, chlorobutanol, chlorhexidine, sorbic acid, benzoic acid, PHB esters or organic mercury compounds. The application of the nasal solutions can be carried out by means of dosing sprays or in the form of nasal drops with an increasing portion of the viscosity or respectively in the form of a nasal gel or a nasal cream. For the application by inhalation, nebulizers or containers with gas under pressure can be used, using inert vehicle gases. For the application of powders intended for nasal or pulmonary inhalation special applicators are needed. The effective dose amounts to at least 0.001 mg / kg / day, preferably at least 0.01 mg / kg / day, at most 3 mg / kg / day, preferably 0.03 to 1 mg / kg / day of body weight, depending on the degree of severity of the symptom-tology, referred to an adult with a body weight of 75 kg.

The abbreviations used for amino acids correspond to the three-letter code that is usual in the chemistry of peptides, as described in Europ. J. Biochem. 138, 9 (1, 984). Other abbreviations used are listed below: Aeg N- (2-aminoethyl) -glycine Cpg cyclopentylglycyl Fmoc 9-fluorenyl-methyloxycarbonyl Nal 2-naphthylalanyl Oic cis-endo-octahydroindol-2-carbonyl Thi 2-thienylalanyl Tic 1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl .

Example 1: Effect of HOE 140 on the segregation of urine and electrolytes in rats with hepatic fibrosis induced by carbon tetrachloride Method: Wistar rats (breeder Hoechst AG, Kasten-grund) with an initial body weight of 120-150 g were used .

Provocation of hepatic fibrosis: A liver fibrosis was induced as described by Bickel et al. , J. Hepatol. , 13 (Supplement 3 (1991) 26-33) The animals received carbon tetrachloride (CC14) twice a week at a dose of 1 ml / kg orally for at least 6 weeks.Fibrosis of the liver was verified at Through the collagen content of the liver and liver parameters relevant to the liver (bilirubin, ALAT, bile acids.) During the course of the fibrogenesis, the animals were kept under normalized conditions, as indicated below: In the rhythm of day-night (clarity phase from 6.30 am to 6.30 pm), room temperature 22 ± 2 ° C and relative humidity of air 60 ± 10% The animals received a normalized feed for rats (Altromin® 1321) and water ad libitum.

Experiment of saluresis and diuresis: At the time of the diuresis experiment, the animals had reached a weight between 200 and 320 g. The feed was subtracted 16 h before the experiment and kept apart throughout the experiment. Free access to water was still allowed to the animals until the actual beginning of the experiment. The animals were kept in special diuresis cages for the duration of the diuresis experiment. A controlled diuresis was provoked with an oral administration of 20 ml of water per kg of body weight at the time 0 h. Segregation of electrolytes and urine volumes was determined in the collection periods of 0-5 and 6-24 h separately for each animal. Five days later, the experiment was carried out again in the same animals by administration of bradykinin antagonists. The animals each received 0.3 mg / kg of HOE 140 s.c. (subcutaneously) at times 0 and 6 h, dissolved in 5 ml of a sodium chloride solution for each kg of body weight Sodium and potassium were determined by flame photometry (flame photometer from Eppendorf, Hamburg) . The chloride was measured argentometrically through a potentiometric determination of the end point (Eppendorf chloride meter, Hamburg). The analytical results were used for the calculation of urine segregation (ml / kg body weight) and electrolyte segregation (mmol / kg body weight).

Results: Table 1: (Mean values (VM) ± DT, n = 1 0) Collection period Collection period 1 - -5 h 6-24 h Witness HOE 1 40 Witness HOE 140 Urine volume VM 1 9.06 26, 59 * 23.29 31, 03 * (ml / kg) DX 5.69 4.82 8, 57 1 1, 81 Sodium VM 0.21 0.48 * 1, 43 4, 10 * * * (mmol / kg) DT 0, 1 6 0, 1 9 0.90 1, 40 Potassium VM 0.43 0.51 2.85 2.10 * (mmol / kg) DT 0.27 0.32 0.85 1, 00 Chloride VM 0.31 0.35 0.87 3.27 * * * (mmol / kg) DT 0.21 0.26 0.35 1, 22 * P • c 0.05; * * p < 0.01; * * * p < 0.001 Statistics: The results are indicated as arithmetic mean and standard deviation (SD). Statistical verification was carried out with the T test, in the case of deviation from the normal distribution, with the non-parametric Mann-Whitney test.

Results and assessment: Animals treated with bradykinin antagonists showed a pronounced increase in sodium segregation in rats with hepatic fibrosis induced by carbon tetrachloride. As an example, experimental data are shown in Table 1 with the bradykinin peptide antagonist HOE 140 (INN Icatibant). A clear and statistically significant natriuresis is revealed. The model of hepatic fibrosis in a rat, induced by carbon tetrachloride, finds general recognition for liver cirrhosis in humans. Excessive sodium retention is characteristic of hepatic fibrosis and liver cirrhosis in humans and animals, and is considered as a sequel to a very pronounced hemodynamic disorder. { Schrier et al, Hepatology 8 (1988) 1 .151 -1. 157). This hemodynamic disorder consists of portal hypertonia (hypertension of the portal venous system), which is closely linked to excessive peripheral vasodilatation, especially in the splanchnic sector (hyperdynamic circulatory situation). The original cause of peripheral vasodilatation has not been explained so far. The pathological retention of sodium and water worsens the symptomatology, contributing p. ex. to the formation of edema and ascites. Portal hypertonia is associated with inadequate peripheral vasodilation and sodium retention. These are responsible for phenomena of decompensation in cases of liver fibrosis and liver cirrhosis. These phenomena of decompensation include not only symptoms such as edema and ascites formation, but also the so-called hepatorenal syndrome (failure and renal failure as a result of a severe liver disease). The strong natriuretic effect of the bradykinin antagonists in the case of rats with hepatic fibrosis and liver cirrhosis is unexpected, since the bradykinin antagonists do not manifest this effect in healthy animals, and, on the contrary, in special hypertonia models can lead even to a decrease in diuresis and sodium segregation [Madeddu et al. , Br. J. Pharmacol. 106 (1992) 380-386; Majima et al. , Hypertension, 22 (1993) 705-714). Indeed, bradykinin can stimulate in the kidney saluresis and diuresis through vascular and tubular mechanisms. Bradykinin is an endogenous peptide with strongly vasodilating properties in different vascular sectors. The results obtained by the authors of the present invention show that bradykinin, with its strongly vasodilating properties, is an essential mediator of excessive sodium retention and pathological vasodilation. An improved hemodynamic situation far outweighs a possible limitation of sodium and water segregation by inhibiting the stimulating effect of endogenous bradykinin in the kidney, resulting in a therapeutic utility. Accordingly, bradykinin antagonists are suitable for therapeutic and preventive treatment in chronic fibrogenetic liver diseases (liver cirrhosis and liver fibrosis) and acute liver diseases, and for the prevention of complications.

Claims (7)

CLAIMS 1. - Use of bradykinin antagonists or their physiologically compatible salts for the preparation of drugs for the treatment of chronic fibrogenetic liver diseases (liver cirrhosis and liver fibrosis) and acute liver diseases, and for the prevention of complications. 2 . - Use according to claim 1 of a bradykinin antagonist of the formula I
1. Z - P - A - B - C - E - F - K - (D) Q - G - M - F '- I (I), wherein Z a-j_) represents hydrogen, (C -) - C8 - alkyl, alkanoyl (C - ^ - Cg), alkoxy (C - j - Cg) - carbonyl, (C3 - C8) cycloalkyl, cycloalkanoyl ( C4-C9) or alkyl (C-j_-Cg) -sulphonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or 3 radicals, equal or different, taken from the series formed by carboxy, NHR (l), [(C 1 -C 4) alkyl] NR (1) or [aryl (C 6 -C 10) -alkyl (C-^^)] NR. { 1), R (l) representing hydrogen or a protecting group of urethane, alkyl (Cj ^ C ^, alkyl (C -] _ Cg) -amino, aryl (Cg-C10) - alkyl (C -) _ C4 ) -amino, hydroxy, (C- ^ - C ^) alkoxy, halogen, di- [(C ^ Cg) alkyl] amino, di- [aryl (Cg-C10) -alkyl (C1-C4) -amino, carbamoyl, phthalimido, 1,8-naphthalimido, sulfamoyl, alkoxy (C ^ C ^) -carbonyl, aryl (Cg-C14) and aryl (Cg-C14) -alkyl (C ^ -Cg), or in which in each case 1 hydrogen atom is optionally replaced by a radical taken from the series consisting of cycloalkyl (C3-Cg), alkyl (C ^ Cg) -sulfonyl, alkyl (C ^ Cg) -sulfinyl, aryl (Cg-C14) -alkyl (C1-C4) -sulfonyl, aryl (Cg-C14) -alkyl (C1-C4) -sulfinyl, aryl (Cg-C14), aryloxy (Cg-C14), heteroaryl (C3-C13) and heteroaryloxy (C3 ~ C13) ) and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals taken from the series consisting of carboxy, amino, alkyl (C ^ Cg) -amino, hydroxy, alkoxy { _ - ^), halogen, gave- [(C 1 -Cg) alkyl] -amino, carbamoyl, sulphamoyl, (C-j-C 4) alkoxycarbonyl, (C 6 -C 14) aryl, and (Cg-C 14) aryl-(C 1 -C 5) alkyl; a2) aryl (Cg-C14), aroyl (C7-C15), aryl (Cg-C14) -sulfonyl, heteroaryl (C3-C13) or heteroaroyl (C3-C13), -a3) carbamoyl, which may optionally be substituted in nitrogen with alkyl (C ^ Cg), aryl (Cg-C14) or aryl (Cg-C14) -alkyl (C1-C5); it being realized, in the radicals defined in sections a-j_), a2) and a3), that the aryl, heteroaryl, aroyl, arylsulfonyl and heteroaroyl groups are optionally substituted with 1, 2, 3 or 4 radicals taken from the series formed by carboxy, amino, nitro, alkyl (C ^ -Cg) -amino, hydroxy, alkyl (C1-Cg), alkoxy (C1-Cg), aryl (C8-C14), aroyl (C7-C15), halogen, cyano, di- [alkyl (C - ^ - Cg)] -amino, carbamoyl, sulphamoyl and (C ^ Cg) alkoxycarbonyl; P a direct link or a radical of formula II,
2. - NR (2) - (U) - CO - (ID wherein R (2) means hydrogen, methyl or a urethane protecting group, U stands for (C3-C8) cycloalkylidene, arylidene (Cg-C14), heteroarylidene (C3-C13), aryl (Cg-C14) -alkylidene ( Cj ^ Cg), which may be optionally substituted, or [CHR (3)] n, where n 1-8, preferably 1-6, meaning R (3), independently of one another, hydrogen, alkyl (C ^) Cg), (C3-C8) cycloalkyl, (Cg-C14) aryl, (C3-C13) heteroaryl, which, with the exception of hydrogen, are in each case optionally monosubstituted with amino, substituted amino, amidino, substituted amidino, hydroxy , carboxy, carbamoyl, guanidino, substituted guanidino, ureido, substituted ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 1,8-naphthalimido, -imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, or in which R (2) and R (3), in common with the atoms that carry, formed a monocyclic, bicyclic or tricyclic ring system with 2 to 15 carbon atoms; A as defined P; B a basic amino acid in the L or D configuration, which may be substituted in the side chain; C a compound of the formula Ill or Illb
3. G'-G'-Gly G'-NH- (CH2) p-C0 (III a) (III b) wherein p is from 2 to 8, and the G ', independently of each other, mean a radical of the formula IV -NR (4) -CHR (5) -C0- (IV) wherein R (4) and R (5), in common with the atoms that carry them, form a monocyclic, bicyclic or tricyclic, heterocyclic ring system with 2 to 15 C atoms; E the radical of an aliphatic or alicyclic-aliphatic, neutral, acid or basic amino acid, -F, independently of each other, the radical of an aliphatic or aromatic, neutral, acid or basic amino acid, which may be substituted in the chain lateral, or a direct bond, - (D) Q D-Tic, D-Phe, D-Oic, D-Thi or D-Nal, which may eventually be substituted with halogen, methyl or methoxy, or a radical of the following formula (V) wherein X represents oxygen, sulfur or a direct bond; R represents hydrogen, (C1-C8) alkyl, (C3-Cg) cycloalkyl, (Cg-C14) aryl, (Cg-C14) aryl, the alicyclic radical being optionally substituted by halogen, methyl or methoxy; G as defined G 'before or a direct bond, -F' as defined F, a radical NH- (CH2) s-, where q = 2 to 8, or, in the case that G does not means no direct bond, a direct bond, - -OH, -NH- or -NHC2H5, K the radical -NH- (CH2)? -CO-, where x = 1-4 or a direct bond, and M as has defined F, as well as its physiologically compatible salts. 3. Use according to claim 2 of a bradykinin antagonist of the formula I, in which they mean: Z hydrogen, or as defined above in a1), a) or a3), P a bond or a radical of formula II
4. - NR (2) - (U) - CO - (||) where U is equal to CHR (3) and R (3) is as previously defined, R (2) is equal to H or CH3, A a bond. 4. Use according to claim 2 of a bradykinin antagonist of the formula I, in which they mean: Z hydrogen or as defined above in a), a2) or a3), P a bond or a radical of formula II
5. - NR (2) - (U) - CO (II) where U is equal to CHR (3) and R (3), independently of each other, means hydrogen, alkyl (C- | _-Cg), cycloalkyl (C3-C8), aryl (Cg-C14), heteroaryl (C3-C13), which with the exception of hydrogen are in each case monosubstituted optionally with amino, substituted amino, hydroxy, carboxy, carbamoyl, guanidino, substituted guanidino, ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl , 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, or in which R (2) and R (3), in common with the atoms that carry them, form a monocyclic, bicyclic or tricyclic ring system with 2 to 15 C atoms, R (2) is equal to H or CH3, -A bond; (D) Q D-Tic. 5. Use of a bradykinin antagonist or its physiologically compatible salts for the preparation of medicaments for the treatment of chronic fibrogenetic liver diseases (liver cirrhosis and hepatic fibrosis) and acute liver diseases, and for the prevention of complications according to claim 2 , characterized in that the bradykinin antagonist is HD-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140), para-guanidobenzoyl-Arg-Pro-Hyp-Gly- Thi-Ser-DTc-Oic-Arg-OH, HD-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-HypE (transpropil) -Oic-Arg-OH, HD-Arg-Arg- Pro-Hyp-Gly-Cpg-Ser-D-Cpg-Cpg-Arg-OH, HD-Arg-Arg-Pro-Pro-Gly-Thi-Ser-DTc-Oic-Arg-OH, H-Arg ( Cough) -Pro-Hyp-Gly-Thi-Ser-DTyc-0¡c-Arg-OH, H-Arg (Cough) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg -OH, HD-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Airg-OH, Fmoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic -Oic-Arg-OH, Fmoc-Aoc-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH, Fmoc-e-aminocaproyl-D-Arg-Arg-Pro - Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH, benzoyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH, cyclohexylcarbonyl-D- Arg-Arg-Pro-Hyp-Gly-Th? '- Ser-D-Tic-Oic-Arg-OH, Fmoc-Aeg (Fmoc) -D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D Tic-Oic-Arg-OH, Fmoc-Aeg (Fmoc) -Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH, ndol-3-yl-acetyl-D-Arg -Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH, dibenzylacetyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-0¡c-Arg -OH
6. 6. - Use of a bradykinin antagonist according to claim 5, characterized in that the bradykinin antagonist is HD-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-0-cA-rg-OH (HOE 140) or para-guanidobenzoyl-Arg-Pro-Hyp-Gly-Thi-Ser-DT'c-Oic-Arg-OH.
7. 7. Use of a bradykinin antagonist according to claim 5, characterized in that the bradykinin antagonist is HD-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DTc-0c-Arg-OH ( HOE 140).