LT3375B - Peptides and pharmaceutical composition containing them - Google Patents

Description

The present invention relates to novel peptides having bradykinin antagonistic activity, as well as to a pharmaceutical composition based thereon.

PCT application no. No. 86/07263 discloses bradykinin antagonist peptides wherein, inter alia, the L-Pro 7 position of the bradykinin peptide hormone bradykinin or its analog is replaced by a D-amino acid, e.g. D-Phe, D-Thi, D-Pal, CDP, MDY, D-Phg, D-His, D-Tp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D- Ile, D-Leu and DOMT.

The object of the present invention was to find novel peptides having bradykinin antagonist properties.

This problem is solved by the help of peptides of the formula:

A-B-C-E-F-K- (D) -Tic-G-M-F'-I (I) wherein

A represents hydrogen, (C 1 -C ₆ ) alkanoyl or (C _x -C ₆ ) alkanoyl substituted by a carboxyl group, or a radical of formula II

R -N-CH-C-

(II) in which

R represents hydrogen, C 1 -C 8 alkanoyl or C 1 -C 8 alkanoyl substituted by hydroxyphenylpropionyl;

R ² represents a hydrogen atom; and

R ³ represents C 1 -C 8 alkyl substituted with amino, guanicide, phenyl substituted with hydroxyl.

B represents a direct bond or a basic amino acid in the L- or D- configuration, said amino acid belonging to Arg, Lys and Orn and can be substituted in the side chain by benzyloxycarbonyl, nitro, tosyl, nicotinoyl, -CO-NH-C ₆ H ₆ or 2, 3,

5-trimethyl-4-methoxyphenylsulfonyl;

C represents a compound of formula IIla

G'-G'-C (IIla) wherein G 'is an independent radical of formula IV

-N-CH-C-

(IV) wherein R ⁴ and R ⁵ together with the other atoms form a heterocyclic, monocyclic system containing 1 nitrogen atom and four carbon atoms, a system which may be substituted by a hydroxy group or a group containing 1 nitrogen atom, 3 carbon atoms and 1 oxygen atom or forming a heterocyclic, bicyclic ring system containing 1 nitrogen atom and 7 carbon atoms;

E represents a Phe, Trn or Thia aromatic amino acid residue of the L- or D- configuration;

F represents the amino acid radical or direct bond of the L- or D- configuration of Ash, Cys, Gln, Orn, Ser, Trp, Phe, Thia.

K represents the radical -NH- (CH ₂ ) _X -CO, where X = 1-2, or represents a direct bond.

(D) - Those refer to the group of formula V

(V)

G represents a direct bond or a radical of formula IV having

-N-CH- οι, ¹ ₅ II

RR ⁵ O wherein R ⁴ and R ⁵ together with the other atoms form a heterocyclic, monocyclic system containing 1 nitrogen atom and four carbon atoms, or a system containing 1 nitrogen atom, 3 carbon atoms and 1 oxygen atom or forming a heterocyclic, bicyclic ring system having 1 nitrogen atom and 7-9 carbon atoms;

F 'represents a residue of the -NH- (CH ₂ ) ₄ -, or L- or D- configuration of the Arg or Ser amino acid radical, which may be substituted by rhamnosyl or 2,3,5-trimethyl-4-methoxyphenylsulfonyl or represents a direct bond;

I represents an amino or hydroxy group or a physiologically acceptable salt thereof.

Unless otherwise stated, the designation of an amino acid radical without a stereo descriptor means that the radical is in L-form (Schröder, Lübke, Peptides, Volume 1, New York, 1965, pp. ΧΧΙΙ-ΧΧΙΙΙ; Houben-Veil, Methods in Organic Chemistry, Vol. XV / 1 and 2, Stuttgart 1974) as an example:

Aad, Abu, yAbu, ABz, ξΑΒζ, ξΑσ3, Ach, Acp, Adpd, Ahb, Aib, AAib, Ala, PAla, Ala, Alg, Ali, Am, Apl, Apm,

Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bhp, Can, Cit, Cys, Cyta, Daad, Dab, Daad, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hClu, His, hlle, hLeu, hLus, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, eHyp, Ile, Ise, Iva, Kyn, Lant, Len, Leu, Lsg, Lys, PLys, Lys, met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pyc, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, pThi, Thr, Thy, Thx, Tia, Tie, Tly, Trp,

Trta, Tyr, Vai.

In formula IV, the radical of the heterocyclic ring system may be the radicals of the following groups of heterocycles:

pyrrolidine (A); piperidine (B); tetrahydroisoquinoline (C); decahydroisoquinoline (D); octahydroindole (E); octahydrocyclopenta (b) -pyrrole (F); 2-azibicyclo (2.2.3) -octane (G); 3-azibicyclo (2.3.1) heptane (H); 2-azispiro (4.4) -nonane (J); spiro (bicyclo (2.2.1) -heptane) -2,3-pyrrolidine) (K); spiro ((bi - cyclo (2.2.2) octane) -2,3-pyrrolidine) (L) 2-azitriciklo (4.3.0.1 ^{6 '9)} decane (M); decahydrocyclohepta (b) pyrrole (N); octahydroisoindole (O); octahydrocyclopenta (c) pyrrole (P); 2,3,3a, 4,5,7a-hexahydroindole (O); tetrahydrothiazole (R); 2-azibicyclo (3.1.0) hexane (S); isoxoazoline (T); pyrazolidine (U); hydroxyproline (V); which may be replaced if necessary.

The heterocycles in the above radicals on page 2a are known from U.S. Pat. 4344349, 4374847, 4350704, EP application no. 50800, 51741, 51080, 49658, 49605, 29488, 46958, 52870, 271865, VFR Application no. 3226768, 3151690, 3210496, 3211397, 3211676, 3227555, 3242151, 2346503 and 3246757.

In addition, some of these heterocycles are disclosed in VFR application no. 3818850.3.

Unless specifically noted, alkyl may have a straight or branched chain of atoms. This also applies to radicals such as alkoxyl, arylalkyl or alkanoyl. (C ₆ -C ₁₂ ) -aryl usually represents phenyl, naphthyl or biphenyl. Correspondingly, more complex radicals such as e.g. aryloxyl, arylalkyl or aroyl.

Halogen means fluorine, chlorine, bromine or iodine, with chlorine being preferred.

Of the salts, the preferred alkali metal salts, or alkaline earth metal salts, salts with physiologically acceptable amines and salts containing residues of organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, citric acid, malonic acid , acetic acid, etc.

More preferred are peptides of formula I wherein

B represents arginine, diaminobutyryl, or the amino group in the side chain, respectively, at aj or a ₂ );

lysine, ornithine, a 2,4L-homoarginine residue, when either the guanidino group is to be replaced by A as described

E represents a radical of an aromatic amino acid residue of the L- or D- configuration which may be substituted on the aryl portion by halogen at the 2, 3 or 4 position, tyrosine, 0-methyl tyrosine, 2-pyridylalanine or naphthylalanine;

F represents a radical of the basic amino acid of the L- or D- configuration, e.g. arginine or lysine, a single guanidine group or an amino group on the side chain may be replaced by A as described in aj or a ₂ ), or represents -NH- (CH ₂ ) _n - where n = 28;

K- represents the radical -NH- (CH ₂ ) _X -CO where X = 2-4, or represents a direct bond. More preferred are compounds of formula I wherein:

B represents arginine, ornithine or lysine when the guanidine group or amino group in the side chain is unsubstituted or substituted by (C ₁ -C ₈ ) -alkanoyl, (C ₇ -C ₁₀ ) aroyl, (C ₃ -C ₈ ) -heteroaryl, ( C ₁ -C ₈ ) -alkisulfonyl or (C ₆ -C ₁₂ ) -arylsulfonyl, where the aryl, heteroaryl, aroyl, arylsulfonyl and heteroarylyl radicals as described in a2) can be replaced by 1, 2, 3 or 4 radicals which are the same or different ;

E represents phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine,

3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, 0-methyl tyrosine or β- (3-tinyl) alanine;

F represents a simple bond; and

M stands for Simple Connection.

Most preferred are peptides of formula I wherein:

A represents hydrogen, (D) - or (L) -H-arginine, (D) or (L) -H-lysine, or (D) - or (L) -H-ornithine;

B represents arginine, ornithine, or lysine, where the guanidine group or the amino group on the side chain may be replaced by hydrogen, (C ₁ -C ₈ ) alkanoyl, (C ₇ -C ₁₃ ) -aryl, (C ₈ -C ₉ ). -heteroaloyl, (C _x C ₈ ) -alkylsulfonyl or (C ₆ -C ₁₂ ) -arylsulfonyl wherein aryl, heteroaryl, aroyl, arylsulfonyl and heteroarylyl radicals may be optionally substituted with 1, 2, 3 or 4 radicals, which may be the same or different. , selected from methoxyl or halogen.

C represents Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;

E represents Phe or Thi;

F represents Ser, Hser, Leu, Lys, Vai, Nle, Ile or Thr;

K represents a simple bond; M represents a simple bond;

G represents a radical of the heterocyclic ring system of formula IV, more preferably the heterocycle radicals to which pyrrolodine (A) belongs; piperidine (B); tetrahydroisoquinoline (C); eis and trans-deca20 hydroisoquinoline (D); cis-endo octahydroindole (E); cis-exi-octahydroindole (E); trans-octahydroindole (E); cis-endo, cis-eski-, trans-octahydrocyclopentane (b) pyrrole (F) or hydroxyproline (V).

F 'represents arginine, and

I stands for OH.

Most suitably, the peptides of formula I are:

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH

H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser (D) -Tic-Oic-Arg-OH

H- (D) -Arg-Arg-Pro-Hyp-Gly-PPhe-Ser (D) -Tic-Oic-Arg-OH

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser (D) -Tic-Oic-Arg-OH

H- (D) -Arg-Arg-Pro-Pro-Gly-Phe-Ser (D) -Tic-Oic-Arg-OH

The present invention relates to a process for the preparation of peptides of formula I which is characterized in that

(a) the moiety or the activated derivative thereof is joined to the corresponding free N-terminal amino group moiety of the C-terminal free carboxyl group, or

b) the stepwise formation of the peptide structure obtained in the compound (a) or (b), respectively, if necessary cleaved, by one or more protecting groups which are attached to protect other functions, and thus converting the compounds of formula I thus obtained , physiologically acceptable salts.

urethane protective butyloxycarbonyl e.g. a tertiary group or

The peptides of the present invention were obtained using known peptide chemical techniques, e.g. by Houbenweyl, Methoden derorganchen Chemie, Band 15/3, B. Merrifield, J. Am. Chem. Soc. 86, 2149 (1963) or

R. C. Shepard, Int. J. Peptide Protein Res. 21, 118 (1983). A protecting group such as (Boc) fluoroethylmethoxycarbonyl (Fmac) is used as an α-amino protecting group. If necessary, e.g. in order to prevent side reactions or to synthesize specific peptides, the functional groups in the amino acid side chains may be protected by appropriate protecting groups (TWGreene, Protective Groups in Organic Synthesis), and in particular Arg (Tos), Arg (Mts), Arg ( mir), Arg (PMC), Asp (OBzl), Asp (OBut), Cys (4-MeBlz), Glu (OBzl), Glu (OBut), His (Tos), His (fmoc),

Lys (Cl-z), Lys (Boc), Met (o),

Thi (Bzl),

Cys (SBut) His (Dnp), Ser (Be),

His (Trt), Ser (Bzl),

Thr (But), Trp (Mts),

Trp (CHO), Tyr (Bzl) or Tyr (But).

Solid phase synthesis begins at the C-terminus of the peptide by binding the protected amino acid to the corresponding resin. Such starting materials may be obtained by coupling a protected amino acid with a modified polystyrene or polyacrylamide resin ester or amide bond via a modified chloromethyl, hydroxymethyl, benzhydrylamine (BHA) or methylbenzhydlamine (MBHA) group. The resins used as the base can be purchased through commercial channels.

BHA- and MBHA- resins are commonly used when the synthesized peptide has a free amide group at the C-terminus. If the peptide has a secondary amide group at the C-terminus, a chloromethyl or hydroxymethyl resin is used and the cleavage is carried out with the appropriate amines. If, for example, ethylamide is desired, the peptide may be separated from the resin by ethylamine and the side-chain protecting group subsequently removed by appropriate reagents. If the peptide amino acid tertiary butyl protecting groups are required to protect the side chain, then the synthesis is carried out with the help of a Fmoco protecting group to temporarily block the α-amino group of the amino acid using the procedure described in FIG. R.C. Sherpard. J. Chem. Soc., Chem. Comm. 1983, 587, wherein the guanidine group of arginine is protected by pyridine perchlorate and other functional groups in the amino acid side chain are protected by benzyl protecting groups which are cleaved by catalytic hydrogenation (A. Felix et al., J. Org. Chem. 13, 4194 (1978). )) or sodium in liquid ammonia (W. Robetrts. J. Am. Chem. Soc. 76, 6303 (1954).

Once the protective amino group of the resin bound amino acid is cleaved, the appropriate reagent, e.g. trifluoroacetic acid in methylene chloride With Boc protecting group) or with 20% piperidine in dimethylformamide solution (in the presence of Fmoc protecting group), the amino acids are sequentially linked in the desired sequence. The peptide resins formed in the intermediate step are deprotected with the reagents described above before binding to the subsequent amino acid derivative.

amino acid racemization

As reactants all activating reagents used in peptide synthesis can be used, e.g. HoubenWeil Methods of Organic Chemistry, vol.15 / 2 such as carbodiimides such as N, N'-dicyclohexylcarbodimide or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide. Coupling with the resin may be accomplished by direct coupling of the derivative with an activating reagent and, if necessary, with an inhibitory additive such as 1-hydroxybenzotriazole (HOBt) (W. Konig, R. Geiger, Chem. Ber. 103, 708 (1970) or

Initial activation of 3-hydroxy-4-oxo by 3,4-dihydrobenzotriazine (HOObt) (W. Konig, R. Geiger, Chem. Ber. 103, 2054 (1970)) as the amino acid as a symmetric anhydride or HOBt or HOObt ester can may be performed separately and such an activated solution may be added to the peptide resin.

The coupling or activation of the amino acid with one of the above activating reagents can be carried out in dimethylformamide, N'-methylpyrrolidone, methylene chloride or a mixture of these solvents. The active amino acid derivative is generally used in an amount of 1.5-4 greater than that required. If an incomplete coupling reaction occurs, it is repeated without deprotection of the amino group of the peptide resin.

The successful course of the reaction can be controlled by the reaction of ninhydrin as described by E. Kaiser et al. Anna. Biochem. 34, 595 (1970). Synthesis can also be automated, e.g. using peptide synthesis programs from Applied Biosystems, both to develop new ones. The latter are required using amino acids protected by Fmoc groups.

After the peptide is synthesized as described above, it can be separated from the resin by liquid fluorine hydrogen (for peptides obtained by the Boc method) or trifluoroacetic acid (for peptides obtained by the Fmoc method). These reagents also cleave other protective side chain groups in addition to the resin peptide. Thus, using BHA- and MBHAdervas, the peptide is obtained in acid form. Using BHA- and MBHA- resins, the peptide is obtained in the form of an acid amide by cleavage with hydrofluoric acid or trifluoroacetic acid. Other methods for obtaining the peptide amide are described in U.S. Patent Application Ser. P37 11 866.8 and P37 43 620.1. Here, the resin separation of the peptide amides is carried out using moderate acids commonly used in peptide synthesis (e.g. trifluoroacetic acid), and compounds such as phenol, cresol, triocresol, anisole, ethanethiol, dimethylsulfide, ethylmethylsulfide and others are used to neutralize the cations. used in such cases, either singly or in combination. Trifluoroacetic acid can be used and diluted with appropriate solvents, e.g. methyl chloride.

If peptide side-chain tertiary butyl or benzyl protecting groups are to be retained, then the synthesized peptide is separated.

1% dilute in methyl chloride with trifluoroacetic acid (R. C. Shepard. J. Chem. Soc. Chem. Comm. 1983, 587). If tertiary butyl or benzyl protecting groups are to be retained, appropriate synthetic separation techniques are employed.

The resin described by Shepard is also used to synthesize the peptides using the C-terminal amide group, the ω-amino or the ω-guanidine alkyl group.

After synthesis, the protected side chain peptide is separated from the resin and further rearranged with the appropriate amino, ω-aminoalkylamine or ω-guanidine alkylamine, and if necessary, other groups can be temporarily protected by known methods.

Another method for the preparation of peptides by the ω-aminoalkyl group is described in VFR patent application no. 36 35 670.0.

The peptides of the invention were synthesized mainly in solid phase by reaction using two protecting group tactics.

The synthesis was carried out by Applied Biosystems Automated Peptide Synthesis Model 430A using the Boc- and Fmoc-protecting group method to temporarily block the amino group.

Synthetic programs prepared by the manufacturer were used using the Boc-protecting group.

Synthesis of peptides with the free carboxylic group at the C-terminus was carried out on the corresponding Boc-amino acid treated

4- (hydroxymethyl) phenylacetamidomethyl-polystyrene resin (R. B. Merrifield. J. Org. Chem. 43, 2845 (1978)) provided by Applied Biosystems. MBHA resin from the same company was used to obtain the peptidamides.

When the reactants used are N, N'-dicyclohexylcarbodiimide or N, N'-diisopropylcarbodiimide. Activation was performed in symmetric anhydride, HOBt-ether, or NMP. The connection was used

2-4 equivalents of the activated amino acid derivative. If the merger reaction was incomplete, it was repeated.

Using the Fmoc-protecting group for the temporary protection of the α-amino group, new synthesis programs have been developed for Applied Biosystems Model 430A. The synthesis was carried out on Bachem p-benzyloxybenzyl alcohol resin (S. Wang. J. Am. Chem. Soc. 95, 1328 (1973)), which was esterified according to known procedures (E. Atherton et al., JCS Chem. Comm. 1981). 336) with the aid of the corresponding amino acid. Activation of the amino acid derivatives in the form of HOBt and HOObt esters was accomplished by addition of a solution of diisopropylcarbodiimide in dimethylformamide in the previously prepared mixture of HOBt or HOObt and an amino acid derivative in the capsules provided by the manufacturer. Similarly, the obtained Fmocamino acid-OObt-esters, as disclosed in application no. 87107634.5.

the cleavage was carried out as described in EP Fmoc-protecting group with 20% piperidine dimethylforamide in the reaction vessel. The excess of the amino acid derivative used was 1.52.5 equivalents. If the merger was incomplete, it was repeated, as in the Boc method.

The peptides of the invention each individually or in combination exhibit bradykinin-antagonistic activity which can be tested in various models (Handbook of Exp. Pharmacol., Vol. 25, Springer Verlag, 1970, S. 53-55), e.g. isolated rat uterus, guinea pig intestine, or guinea pig isolated pulmonary artery.

In testing the peptides of the invention, guinea pigs weighing 400450 g in the isolated pulmonary artery (Dunkin. Hartley) are killed by an impact on the occiput.

The thorax is opened and the pulmonary artery is carefully removed. Circumjacent tissues 45 are removed and the artery is cut spirally at an angle of ^0.

The resulting arterial strip is 2.5 cm long and 3-4 cm wide and fixed in a 10 ml organic bath filled with solution.

Composition of solution in mmol / l

NaCl 154 KCl 5.6 CaCl ₂ 1.9 NaHCO ₃ 2.4 glucose 5.0

Pass 95% O ₂ /5% CO ₂ through the solution and heat to 37 ° C. Hydrogen index is 7.4 and initial load on arterial bar is 1.0 g.

Isotonic contractions are recorded using a Hug Zax HF modem and recorded with a compensator (BEC, Coerc Metrawatt SE460).

After one hour equilibrium is reached, the test begins. After the bands reach the highest sensitivity of 2x10 ⁷ mol / L bradykinin (bradykinin induces contraction of the arterial bands), a dose of 5χ10 ′ ^θ -5x100 ⁵ mol / L is applied for 10 minutes and a reduction in its efficacy is detected after a new dose of bradykinin. with a control sample.

Peptides ^_ 5 ^_ 3 are used in doses of 1x10 -1x10 mol / l to determine the partial antagonistic effect.

The calculated IC ₅₀ values for the peptides of the invention based on the dose response graphs are shown in Table 1.

Compound IC ₅₀

H- (D) -Arg-Arg-Hyp-Pro-Gly'-Phe-Ser- (D) -Tic-Phe-Arg-OH 4,6x10 ~ ⁶ H- (D) -Arg-Arg-Hyp-Pro -Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH 2,1x10 ⁶ H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe- Arg-OH 1.2x10 ⁵ H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Glo- (D) -Tic-Phe-Arg-OH 2.4x10 ⁵ H- (D) -Arg -Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mts) -OH 2.5x10 ⁵ H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe- Ser- (D) -Tic-Pro-Arg-OH 2.5x10 ⁷ H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH 1 , 9x10 ⁷ H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH 5,6x10 ⁷ H- (D) -Arg-Arg- Hyp-Pro-Gly? -Ma-Ser-p-Ala- (D) -Tic-Aoc-Arg-OH 1.7x10 ~ ⁶

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D) -Tic-AOC-Arg-OH 3, 9xl0 ~ ⁷ H- (D) -Arg-Arg-Hyp- Pro-Gly-Thia-Gly- (D) -Oic-Arg-OH 3.2x10 ⁷

H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH 4, 810-7

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH 1.7x10 ⁷ H- (D) -Arg-Arg-Pro-Hyp-Gly -Thia-Ser- (D) -Tic-Aoc-Arg-OH 1, ΙχΙΟ'θ H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg -OH 4.6x10 ⁸ H- (D) -Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH 6.2x10 ⁸ H- (D) -Arg- Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tie- (D) -Oic-Arg-OH 2, 6x10 ⁹ H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser - (D) -Tic-Oic-Arg-OH 5.4x10 ⁹ H- (D) -Arg-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH 3.2x10 ⁷ H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH 6,8x10 ⁹ H- (D) -Arg-Arg- (NO 2) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH 6,4x10 ⁸

H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH 4,2x10

H- (D) -Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH 3.4x10

H- (D) -Arg- (Tos) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Dic-Arg-OH 3.0x10

H- (D) -Arg- (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Dic-Arg-OH 1.8x10

Therapeutic use of the peptides of the invention is possible in pathological situations caused by bradykinin or related peptides. This includes injuries such as wounds, burns, rashes, bumps, angina, arthritis, asthma, allergic conditions, rhinitis, shock, inflammation, low blood pressure, pain, etc.

Therefore, the invention also relates to the use of formula I pethides as pharmaceutical therapeutic agents for the activation of these peptides.

Pharmaceutical formulations contain an effective amount of a Formula I biologically active substance, either alone or in admixture, in combination with an inorganic or organic pharmaceutically acceptable pharmaceutical base.

The formulations may be administered enterally, parenterally, e.g. administered subcutaneously, intramuscularly or intravenously under the tongue, nose, rectum, vagina, by inhalation. The dosage of the biologically active product depends on the species, body weight, age and route of administration of the warm-blooded animal.

The pharmaceutical preparations of the invention are prepared according to known procedures as solutions, formulations, granules or dragees.

when the active compounds are administered orally or in mucous membranes, the compounds are admixed with conventional excipients such as carriers, stabilizers or inert solvents, and are formulated, in known manner, in the form of tablets, capsules, dragees, aqueous, alcoholic or oily solutions or suspensions. carriers include gum arabic, magnesium, magnesium carbonate, potassium phosphate, sucrose, glucose, or starch, e.g. corn starch. The product can be either dry or wet granules. Vegetable oils or animal fats may be used as fat carriers or solvents, e.g. sunflower oil and fish oil.

For topical use, the preparation may be in the form of an aqueous or oily solution, cream, emulsion, gel, ointment and, where appropriate, in the form of a water-air mixture, whereby binding may be improved by the addition of polymeric substances.

For nasal administration, the compounds are mixed with the substances used for this purpose as stabilizers and inert solvents and converted, by standard methods, to aqueous, alcoholic, fatty or aqueous, oily, fatty solutions. Ethylenediamine-N, N, N ', N'-tetracetic acid, citric acid or their salts may be added to aqueous preparations for nasal administration. Nasal delivery can be achieved using dispenser-sprayers or a possible delivery in the form of nasal drops, nasal creams.

Inhalation may be done using nebulizers or compressed inert gas containers. Intravenous, subcutaneous, subcutaneous or subcutaneous administration of the biologically active agents or their physiologically acceptable salts may be combined with excipients.

Due to the short half-life of some of the described medicinal products in the body, it is advisable to use decelerating agents.

The pharmaceutical forms may be e.g. crystalline fat suspensions, microcapsules, sticks or impantants, which may be made from their biodegradable polymers, such as copolymers of polylactic acid and polyglycolic acid or human albumin.

Suitable concentrations for topical and inhalation administration are in the range of 0.01 - 5 mg / ml, and for systemic administration, 0.01 - 10 mg / kg.

List of abbreviations

The amino acid certificates used in the abbreviations correspond to the three-character coding used in chemistry as described in Europ. J. Biochem. 138, 9, (1984). Other abbreviations used are listed below.

Acm acetamidomethyl e-Ahx ε-aminohexanoyl

Aoc eis, endo-3-azabicyclo (3.3.0) octane-3-S-carbonyl

Hoc tertiary butyloxycarbonyl

To be tertiary butyl

Bzl Benzyl

Cl-z 4-chloro-benzyloxycarbonyl

DMF dimethylforamide

Dnp 2,4-dinitrophenyl

Fmoc

Me

4-Mebzl

Mtr

Mts

NMP

Oic

Opr

Pmc

T FA

Tcs

Thia

They

Trt

9-fluorenylmethyloxycarbonyl methyl

4-methylbenzyl

4-methoxy-2,3,6-trimethylphenylsulfonyl mesitylene-2-sulfonyl

N-methylpyrrolidine cis-endo-octahydroindole-2-carbonyl isoxazolidin-3-ylcarbonyl

2,2,5,7,8-Pentamethylchroman-6-sulfonyl trifluoroacetic acid

4-methylphenylsulfonyl

2-thienylalanil

1,2,3,4-Tetrahydroisoquinolin-3-ylcarbonyl trityl

The following examples illustrate possible solid phase peptide synthesis methods of the invention without limiting the scope of the present invention.

The following amino acid derivatives were used:

Fmoc-Arg (Mtr) -OH, Boc (D) -Arg-OH, Fmoc-Arg (Pmc) -OH, Fmoc-Hyp-OH, Fmoc-Pro-OObt, Fmoc-Gly-OObt, Fmoc-Phe10 OObt, Fmoc-Ser (tBu) -OObt, Fmoc-(D) -Tic-OH, Fmoc-Gln-OH, Fmoc-Aoc-OH, Fmoc-Thia-OH, Fmoc-Opr-OH, Fmoc- (D) -AsnOH , Fmoc-p-Ala-Oh, Fmoc-Oic-OH.

Example 1

The compound H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-PheArg-OH was synthesized using Applied Biosystems Model 430A using the Fmoc-method of the Fmoc-Arg (Mtr) ester. -OH in p-benzyloxybenzyl alcohol resin from Novabiochem (loading 0.5 mmol / g resin). 1 g of resin was used and synthesis was carried out according to a modified Fmoc-synthesis program.

The synthesizer cartridge contained 1 mmol of an amino acid derivative with a free carboxyl group. 0.95 mmol HOCbt was co-introduced. Initial activation of these amino acids was performed in a cartridge by dissolving 4 mL of dimethylforamide and adding 2 mL of 0.55 molar solution of diisopropylcarbodiimide in dimethylforamide.

The HOCbt-esters of the other amino acids were dissolved in 6 mL of N-methylpyrrolidine and combined as the activated amino acids with the de-blocked 20% piperidine solution in dimethylformamide resin. Upon completion of the synthesis, the peptide was separated from the resin by removal of the side chain protecting groups with trifluoroacetic acid using thionizole and ethanedithiol. The product obtained after trituration with trifluoroacetic acid was repeatedly treated with acetic acid ester and centrifuged. The remaining product was chromatographed on a Sefadex ZH ₂ 0 column eluting with 10%

acetic acid. Containing bound and dried pure peptide fractions MS (FAB): 1984 (M + H) @ + The following 2-24 examples peptides were to produce

analogously to Example 1.

Example 2

H- (D) -Arg-Arg-Hyp-Pro-Gly-Pro- (D) -Ser- (D) -Tic-Phe-Arg-OH

MS (FAB): 1294 (M + H) @ +.

Example 3

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH.

MS (FAB): 1306 (M + H) @ +.

Example 4

H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH.

MS (FAB): 1294 (M + H) @ +.

Example 5

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Gly- (D) -Tic-Phe-Arg-OH.

MS (FAB): 1335 (M + H) @ +.

Example 6

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1244 (M + H) @ +.

Example 7

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Trp- (D) -Tic-Phe-Arg-OH.

MS (FAB): 1393 (M + H) @ +.

Example 8

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1250 (M + H) @ +.

Example 9

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Arg- (D) -Tic-Thia-Arg-OH.

MS (FAB): 1333 (M + H) @ +.

Example 10

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Opr- (D) -Tic-Thia-Arg-OH.

MS (FAB): 1301 (M + H) @ +.

Example 11

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Gln- (D) -Tic-Thia-Arg-OH.

MS (FAB): 1347 (M + H) @ +.

Example 12

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D) -Tic-Pro-ArgOH.

MS (FAB): 1307 (M + H) @ +.

Example 13

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-OH.

MS (FAB): 1241 (M + H) @ +.

Example 14

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-Arg-OH.

MS (FAB): 1397 (M + H) @ +.

Example 15

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-p-Ala- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1321 (M + H) @ +.

Example 16

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D) -Tic-Pro-Arg-Oh.

MS (FAB): 1230 (M + H) @ +.

Example 17

H- (D) -Aoc-Pro-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH.

MS (FAB): 1330 (M + H) @ +.

Example 18

H- (D) -Arg-Arg-Pro-Aoc-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH.

MS (FAB): 1330 (M + H) @ +.

Example 19

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1290 (M + H) @ +.

Example 20

H- (D) -Arg-Arg-Opr-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1236 (M + H) @ +.

Example 21

H- (D) -Arg-Arg-Pro-Opr-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1236 (M + H) @ +.

Example 22

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Opr-Arg-OH.

MS (FAB): 125 (M + H) @ +.

Example 23

H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1290 (M + H) @ +.

Example 24

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1290 (M + H) @ +.

Examples 25-27

H- (D) -Arg-Arg- (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH and

H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH and

H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH was prepared analogously to 1 but deprotection of the peptide. cleavage of side chains and peptide from the resin with trifluoroacetic acid was restricted for 30 minutes at room temperature. Under these conditions, an arginine cleavage of the Mt protecting group occurs which can be overlooked. The partially deprotected peptides are purified by chromatography.

25: H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH.

MS (FAB): 1506 (M + H) @ +.

26: H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Fhe-Sre- (D) -Tic-Ehe-Arg (Mtr) -OH.

MS (FAB): 1718 (M + H) @ +.

27: H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg (Mtr) -OH.

MS (FAB): 1506 (M + H) @ +.

Peptides 28 to 31 of the following Examples were prepared and purified as in Examples 25 to 27.

Example 28

H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1462 (M + H) @ +.

Example 29

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg (Mtr) -OH.

MS (FAB): 1462 (M + H) @ +.

Example 30

H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-OH.

MS (FAB): 1453 (M + H) @ +.

Example 31

H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1502 (M + H) @ +.

Example 32

H-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH ₂ ) ₄ -NH ₂ .

Peptide synthesis was carried out on 1 g of aminomethyl resin which was modified according to EP application no. 264802, group

C /

Fmoc-NH- (CH ₂ ) ₄ -NH-CO-O-CH ₂ -C

C

C \

CO-CH ₂ -CH ₂ -CO // c

and using Fmoc-amino acid-OOBt esters using an automated peptide synthesizer (Applied Biosystems Model 430A) and proprietary modified synthesis programs. For this purpose, 1 mmol of the corresponding amino acid derivative together with 0.95 mmol of Fmoc-Arg (Mtr) OH, Fmoc-Hyp-OH and Fmoc- (D) -Tic-OH was placed in the synthesis cartridge. Initial activation of the reikaLT 3375 B site was accomplished by dissolving the amino acids in the cartridge, adding 4 ml of dimethylforamide and adding 2 ml of a 0.55 molar solution of diisopropylcarbodiimide in dimethylformamide. The HOCbt-esters of the other amino acids were dissolved in 6 ml of N-methylpyrrolidine and then double-coupled, as were the activated amino acid molecules. After synthesis, the peptide-4-amino-butylamide was isolated from the resin, with the removal of side protecting groups with trifluoroacetic acid. Thioanisole and m-cresol are used to bind cations. The product obtained after trituration with trifluoroacetic acid was treated with acetic acid ester and centrifuged. The remaining product was chromatographed on a Sefadex S25 column eluting with 1N acetic acid. Fractions containing the pure peptide were pooled and dried.

An analogous procedure to Example 32 was also used in Examples 33-35.

Example 33

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH ₂ ) ₄ -NH ₂ .

Example 34

HOOC- (CH ₂ ) ₂ -O-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH ₂ ) ₄ -NH ₂ .

Example 35

H3DC- (CE) ₂ -CD- (D) -Arg-Hyp-Pro-Gly-Ehe-Ser- (D) -Tic-Fhe ^ H- (Cl) ₄ -Nfis.

Examples 36-161 were synthesized according to the procedure described in Example 1.

Example 36

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1307 (M + H) @ +.

Example 37

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser-Gly- (D) -Tic-Pro-Arg-OH.

MS (FAB): 1307 (M + H) @ +.

Example 38

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Phe-OH.

MS (FAB): 1241 (M + H) @ +.

Example 39

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-p-Ala- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1361 (M + H) @ +.

Example 40

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser-p-Ala- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1361 (M + H) @ +.

Example 41

H- (D) -Arg-Arg-Hyp-Pro) Gly-Thia-Ser- (D) -Tic-Pro-Phe-Arg-OH.

MS (FAB): 1397 (M + H) @ +.

Example 42

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Pro-Phe-Arg-OH.

MS (FAB): 1397 (M + H) @ +.

Example 43

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Gly- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1260 (M + H) @ +.

Example 44

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1260 (M + H) @ +.

Example 4 5

H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1390 (M + H) @ +.

Example 46

H- (D) -Arg- (D) -Arg-Phe-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1290 (M + H) @ +.

Example 47

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH.

MS (FAB): 1312 (M + H) @ +.

Example 48

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH.

MS (FAB): 1312 (M + H) @ +.

Example 49

H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1274 (M + H) @ +.

Example 50

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Aoc-Arg-OH.

MS (FAB): 1203 (M + H) @ +.

Example 51

H- (D) -Arg-Arg-Hyp-Pro-Gly-Aoc-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1274 (M + H) @ +.

Example 52

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-p-Ala- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1274 (M + H) @ +.

Example 53

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-p-Ala- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1274 (M + H) @ +.

Example 54

H- (D) -Arg-Arg-Hyp-Pro-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1252 (M + H) @ +.

Example 55

H- (D) -Arg-Arg-Pro-Hyp-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1252 (M + H) @ +.

Example 56

H- (D) -Arg-Arg-Hyp-Pro-Gly-Trp-Ser- (D) -Tic-Aoc-Arg-OH.

MS FAB): 1323.7 (M + H).

Example 57

H- (D) -Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1297.7 (M + H) @ +.

Example 58

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tia- (D) -Oic-Arg-OH.

MS (FAB): 1304.6 (M + H) @ +.

Example 59

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1304.6 (M + H) @ +.

H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

Example 60

MS (FAB): 1289 (M + H) @ +.

Example 61

H- (D) -Arg-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-Oh.

MS (FAB): 1262 (M + H) @ +.

Example 62

H- (D) -Arg-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1276 (M + H) @ +.

Example 63

H- (D) -Arg-Lys-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1260 (M + H) @ +.

Example 64

H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1298 (M + H) @ +.

Example 65

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH>

MS (FAB): 1298 (M + H) @ +.

Example 66

H- (D) -Arg-Arg-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1282 (M + H) @ +.

Example 67

H- (D) -Arg-Arg- (NO ₂ ) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1329.7 (M + H) @ +.

Example 68

H- (D) -Arg-Arg- (NO ₂ ) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1343 (M + H) @ +.

Example 69

H - (FAB): 1327 (M + H).

Example 70

H- (D) -Arg-Arg- (NO ₂ ) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1333 (M + H) @ +.

Example 71

H- (D) -Arg-Arg (NO ₂ ) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 13449 (M + H) @ +.

Example 72

Η-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1302 (M + H) @ +.

Example 73

H-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-Oh.

MS (FAB): 1147 (M + H) @ +.

Example 74

Η-Lys (-CO-NH-C ₆ H ₅ ) -Pro-Hyp-Gly-D-Tic-Oic-Arg-OH.

MS (FAB): 1233 (M + H) @ +.

Example 75

Η-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1296 (M + H) @ +.

Example 76

Β-Lys (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1219 (M + H) @ +.

Example 77

Η-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1282 (M + H) @ +.

Example 78

Ac-Arg- (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1324 (M + H) @ +.

Example 79

H-D-Arg-Arg (Tos) -Phe-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1438 (M + H) @ +.

Example 60

H-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1303 (M + H) @ +.

Example 81

H-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1142 (M + H) @ +.

Example 82

Η-Lys (-CO-NH-C ₆ H ₅ ) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1233 (M + H) @ +.

Example 83

Η-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1296 (M + H) @ +.

Example 84

Η-Lys (nicotinoyl) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1219 (M + H) @ +.

Example 85

H-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1282 (M + H) @ +.

Example 86

Ac-Arg (Tos) -Hyp-Pr) -Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): (M + H) @ +.

Example 87

H-D-Arg-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): (M + H) @ +.

Example 88

H-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): (M + H) @ +.

Example 89

H-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1126 (M + H) @ +.

Example 90

Η-Lys (-CO-NH-C ₆ H ₅ ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1217 (M + H) @ +.

Example 91

Ar-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1280 (M + H) @ +.

Example 92

Η-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1203 (M + H) @ +.

Example 93

Η-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1266 (M + H) @ +.

Example 94

Ac-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1308 (M + H) @ +.

Example 95

Η-Arg-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1422 (M + H) @ +.

Example 96

H-Arg-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1148 (M + H) @ +.

Example 97

Η-Lys (-CO-NH-C ₆ H ₅ ) -Pro-Hyp-Gly-Thia) Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1239 (M + H) @ +.

Example 98

Α-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): (M + H) @ +.

Example 99

H-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1288 (M + H) @ +.

Example 100

Ac-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1330 (M + H) @ +.

Example 101

H-D-Arg-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1444 (M + H) @ +.

Example 102

H-Arg-Hyp-Pro-Thia-Ser-Tic-Oic-Arg-OH.

MS (FAB): 1148 (M + H) @ +.

Example 103

Η-Lys (-CO-NH-C ₆ H ₅ ) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1239 (M + H) @ +.

Example 104

Β-Lys (nicotinoyl) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1225 (M + H) @ +.

Example 105

H-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1289 (M + H) @ +.

Example 106

Ac-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1330 (M + H) @ +.

Example 107

H-D-Arg-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1440 (M + H) @ +.

Example 108

Η-Lys (-CO-NH-C ₆ H ₅ ) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1225 (M + H) @ +.

Example 109

Β-Lys (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Oic-Arg-OH.

MS (FAB): 1209 (M + H) @ +.

Example 110

Η-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tip-Aoc-Arg-OH.

MS (FAB): 1272 (M + H) @ +.

Example 111

Ac-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg) OH.

MS (FAB): 1314 (M + H) @ +.

Example 112

H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH.

MS (FAB): 1428 (M + H) @ +.

Example 113

H-D-Arg-Lys (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1365 (M + H) @ +.

Example 114

H-D-Arg-Lys (-OD-NH-CgHs) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1379 (M + H) @ +.

Example 115

H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1442 (M + H) @ +.

Example 116

H-Lys-Lys- (Nocotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1337 (M + H) @ +.

Example 117

H-Lys-Lys (-CO-NH-CgH1) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1351 (M + H) @ +.

Example 118

H-Lys-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1414 (M + H) @ +.

Example 119

H-D-Arg-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Oic-Arg-OH.

MS (FAB): 1381 (M + H) @ +.

Example 120

H-D-Arg-Lys (-OO-NH-CgHj) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1395 (M + H) @ +.

Example 121

H-D-Arg-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1458 (M + H) @ +.

Example 122

H-Lys-Lys (-GO-NH-CgHs) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1367 (M + H) @ +.

Example 123

H-Lys-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1353 (M + H) @ +.

Example 124

H-Lys-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1420 (M + H) @ +.

Example 125

H-D-Arg-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1359 (M + H) @ +.

Example 126

HD-Arg-Lys (-CO-NH-C ₆ H ₅ ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1373 (M + H) @ +.

Example 127

H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1436 (M + H) @ +.

Example 128

H-Lys-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1331 (M + H) @ +.

Example 129

H-Lys-Lys (-CO-NH-C ₆ H ₅ ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1345 (M + H) @ +.

Example 130

H-Lys-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1408 (M + H) @ +.

Example 131

H-D-Arg-Lys (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FABO: 1375 (M + H) @ +).

Example 132

HD-Arg-Lys (-OO-NH-C ₆ H ₅ ) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1389 (M + H) @ +.

Example 133

H-D-Arg-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1452 (M + H) @ +.

Example 134

H-Lys-Lys (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1347 (M + H) @ +.

Example 135

H-Lys-Lys (-CO-NH-C ₆ H ₅ ) -Pro-Hyp-Gly-Phe-Ser-S-Tic-Oic-Arg-OH.

MS (FAB): 1361 (M + H) @ +.

Example 136

H-Lys-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1424 (M + H) @ +.

Example 137

H-D-Arg-Om (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg) OH.

MS (FAB): 1351 (M + H) @ +.

Example 138

HD-Arg-Om (Tos) -CD-NH-CgHs) ^- Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1428 (M + H) @ +.

Example 139

H-Lys-Om (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1328 (M + H) @ +.

Example 140

Η-Lys-Orn (-αθ-ΝΗ-ΟθΗ ₅ ) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1337 (M + H) @ +.

Example 141

H-D-Arg-Om (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1367 (M + H) @ +.

Example 142

H-D-Arg-Orn-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1381 (M + H) @ +.

Example 143

H-Lys-Om (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1339 (M + H) @ +.

Example 144

H-Lys-Orn (CO-NH-C ₆ H ₅ ) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Arg-OH.

MS (FAB): 1353 (M + H) @ +.

Example 145

H-D-Arg-Om (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1345 (M + H) @ +.

Example 146

H-D-Arg-Orn (OO-NH-CgH1) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1359 (M + H) @ +.

Example 147

H-Lys-Orn (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1317 (M + H) @ +.

Example 148

H-Lys-Orn (CO-NH-C ₆ H ₅ ) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1331 (M + H) @ +.

Example 149

H-D-Arg-Om (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1361 (M + H) @ +.

Example 150

HD-Arg-Orn (CO-NH-C ₆ H ₅ ) -Pro-Hyp-Gly-Phe-Ser-Tic-Oic-Arg-OH.

MS (FAB): 1375 (M + H) @ +.

Example 151

H-Lys-Om (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1333 (M + H) @ +.

Example 152

H-Lys-Orn (CO-NH-C ₆ H ₅ ) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH.

MS (FAB): 1347 (M + H) @ +.

Example 153

H-Lys-Lys-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1218 (M + H) @ +.

Example 154

H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1234 (M + H) @ +.

Example 155

H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1234 (M + H) @ +.

Example 156

H-Lys-Lys-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1212 (M + H) @ +.

Example 157

H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH.

MS (FAB): 1228 (M + H) @ +.

Example 158

H-Lys-Lys-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1232 (M + H) @ +.

Example 159

H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1248 (M + H) @ +.

Example 160

H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1226 (M + H) @ +.

Example 161

H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH.

MS (FAB): 1243 (M + H) @ +.

Examples 162-164 were obtained by analogy to Example 31 using the method described in EP application no. 322348 resin having a structure

Polystyrene

Example 162

HD-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH ₂ .

MS (FAB): 1283 (M + H) @ +.

Example 163

HD-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH ₂ .

MS (FAB): 1283 (M + H) @ +.

Example 164

HD-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH ₂ .

MS (FAB): 1267 (M + H) @ +.

Claims (8)

DEFINITION OF INVENTION Peptides of the formula I A-B-C-E-F-K- (D) -Tic-G-M-F-I (I) wherein A represents hydrogen, (1-6) C-alkanoyl or (1-6) C-alkanoyl substituted with a carboxyl group, or a radical of formula II R ¹ -N-CH-CΙ, Ι, ΙΙ dU, RRO wherein R ¹ represents hydrogen, (1-6) C-alkanoyl or (16) C-alkanoyl substituted by hydroxyphenylpropionyl; R represents a hydrogen atom; and R ³ represents (1-6) C-alkyl substituted with amino guanidine, phenyl substituted with hydroxyl; B represents a direct bond or a basic amino acid in the L- or D-configuration, said amino acid belonging to Arg, Lys and Orn and can be substituted in the side chain by benzyloxycarbanyl, nitro, tosyl, nicotinoyl, CO-NH-C ₆ H ₅ or 2 , 3,5-trimethyl-4-methoxyphenylsulfonyl; C represents a compound of formula Illa G'-G'-Cl (IIla) wherein G 'is independently a radical of formula IV -N-CH-C- (IV) wherein R ⁴ and R ⁵ together with the other atoms form a heterocyclic, monocyclic system containing 1 nitrogen atom and 4 carbon atoms, a system which may be substituted by a hydroxy group or a group containing 1 nitrogen atom, 3 carbon atoms and 1 oxygen atom or forming a heterocyclic bicyclic ring system containing 1 nitrogen atom and 7 carbon atoms; E represents an aromatic amino acid residue of the α- or D-configuration of Phe, Trn, or Thia; F represents an amino acid radical or direct bond of the L- or D-configuration of Asn, Cys, Gln, Orn, Ser, Trp, Phe, Thia; K represents a radical -NH- (CH ₂ ) _X -CO where x = 1-2, or a direct bond; (D) -Tie represents a radical of formula V O (V) G represents a direct bond or radical of formula IV -N-CN-CR ⁴ R ⁵ O 4 5 wherein R and R together with the other atoms form a heterocyclic monocyclic system containing 1 nitrogen atom and 4 carbon atoms or a system containing 1 nitrogen atom, 3 carbon atoms and 1 oxygen atom or forming a heterocyclic bicyclic ring system containing 1 nitrogen atom and 7-9 carbon atoms; F * represents an amino acid radical of the -NH- (CH ₂ ) ₄ -, or L- or D-configuration, Arg or Ser, which may be substituted by rhamnosyl or 2,3,5-trimethyl-4-methoxyphenylsulfonyl or represents a direct bond; 1. represents an amino or hydroxy group and their physiologically acceptable salts. 2. The peptides of the formula I according to claim 1, characterized in that they contain A represents hydrogen, acetyl, 3-carboxypropionyl, or an amino acid of the L- or D-configuration, which may be Arg, Lys, Tyr and may be substituted by hydroxyphenylpropionyl; B represents Arg, Arg (Mtr), Arg (NO ₂ ), Arg (Tos), Lys, Lys (O-NH-CgHj), Lys (z), Lys (Nic), Om (Nic) or Om (-CD). -NH-CgH ₅ ) wherein Arg, Lys and Orn may be in the L- or D-configuration; C represents a compound of formula Illa G'-G'-Cl (IIla) wherein G 'represents an imino acid of the L- or D-configuration which may be Hyp, Pro, Aoc, Opr and dihydroPro; E represents an aromatic amino acid of the L- or D-configuration which may be Phe, Thia and Trp; F represents L- or D-configurations may be Asn, Cys, Gln, Opr, Ser, or represents a direct bond; the amino acid that Trp, Phe and Thia, K represents a radical -NH- (CH ₂ ) _X -CO where x = 1-2, or represents a direct bond; G represents a direct bond or an imino acid of the L- or D-configuration which can be Pro, Aoc, Opr, Tie and Oic; F 'represents an amino acid of the -NH- (CH ₂ ) ₄ - or L- or D-configuration which may be Arg, Arg (Mtr) and Ser or represents a direct bond; to represents an amino or hydroxy group, and physiologically acceptable salts thereof. 3. The peptides of formula I according to claims 1 and 2, characterized in that they contain A represents hydrogen, acetyl, 3-carboxypropionyl, Arg, (D) -Arg, (D) -Tyr, Lys, acetyl- (D) -Arg or 4-hydroxyphenylpropionyl- (D) -Arg; B represents Arg, D-Arg, Arg (Mtr), Arg (NO ₂ ), Arg (Tos), Lys, Lys (z), Lys (Nic), Lys (PAC), Orn (Nic) or Orn (PAC) , or represents a direct connection; C represents Hyp-Pro-Gly, Pro-Hyp-Gly, Pro-Aoc-Gly, OprPro-Gly, Pro-Opr-Gly, Pro-Pro-Gly, Dehydro-Pro-Hyp-Gly or D-Pro-Hyp- Gly; E represents Phe, Thia, (D) -Thia, or Trp; F represents (D) Asn, Cys, Gln, (D) -Gln, Opr, Ser, (D) -Ser, Trp, Phe or Thia, or represents a direct bond; K represents Gly or b-Ala or represents a direct bond; G represents Pro, Aoc, (D) -Aoc, Opr, Tie, Oic, (D) -Oic, (D, L) -Oic, (L) - (3aR, 7aS) Oic or (L) - (3as, 7ar) Oic or represents a direct bond; to represents an amino or hydroxy group, and physiologically acceptable salts thereof. 4. A peptide of the formula I as claimed in claims 1-3, characterized in that it can be: H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH H- (D) -Arg-Arg-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH and a physiologically acceptable salt thereof. 5. A peptide of the formula I as claimed in claims 1-4, which is H- (D) -ArgArg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH and its physiologically acceptable salt. 6. A peptide according to claims 1-5, wherein it is present H- (D) -Arg-Arg-Hyp-Pro-Gly-Aoc-Ser- (D) -Tic-Aoc-Arg-OH H- (D) -Arg-Arg-Hyp-Pro-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH H- (D) -Arg-Arg-Pro-Hyp-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH H- (D) -Arg-Ser- (Rha) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH 5- (4-benzoylphenoxyacetyl) - (D) -Arg-Arg- Pro-Hyp-Gly-ThiaSer- (D) -Tic-Aoc-Arg-OH Lys (benzoyl-benzoyl) - (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser10 (D) -Tic-Aoc-Arg-OH. A peptide of the formula I according to claims 1-6 for pathological states induced by bradykinin and bradykinin related peptides, 15 treat. 8. A pharmaceutical composition for treating pathological conditions caused by bradykinin and bradykinin related peptides, characterized in that: 20 contains an effective amount of the Formula I peptides of claims 1-7, alone or in combination with inorganic and organic pharmaceutical carriers.