FI94353B - Process for the preparation of a therapeutically useful bradyxinin antagonist - Google Patents

Abstract

Peptides of the formula I A-B-C-E-F-K-(D)-Tic-G-M-F'-I (I> in which A is hydrogen, alkyl, alkanoyl, alkoxycarbonyl, alkylsulphonyl, cycloalkyl, aryl, arylsulphonyl, heteroaryl or an amino acid, each of which can optionally be substituted, B is a basic amino acid, C is a di- or tripeptide, E is the residue of an aromatic amino acid, F is, independently of one another, an amino acid which is optionally substituted in the side chain or is a direct bond, G is an amino acid, F' is defined as F, can be -NH-(CH2)2-8 or optionally a direct bond, I is -OH, -NH2 or -NHC2H5 and K is a radical -NH(CH2)-1-4-CO- or is a direct bond, have bradykinin-antagonistic action. Their therapeutic uses comprise all pathological states which are promoted, induced or sustained by bradykinin and bradykinin- related peptides. The peptides of the formula I are prepared by known methods of peptide synthesis.

Description

94355

A method of making a therapeutically useful bradykinin antagonist

The invention relates to a process for the preparation of novel peptides having an opposite effect to bradykinin.

WO 86/07263 describes peptides having an effect on bradykinin in which the peptide hormone bradykinin or other bradykinin analogs, including the 7-position L-Pro, have been replaced by a D-amino moiety such as D-Phe, D-Thi, D-Pal , CDF, D-Nal, MDY, D-Phg, D-His, D-Trp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D-Ile, D-Leu and DOMT .

It is an object of the invention to provide new active peptides which have an opposite effect to bradykinin.

The present invention differs from the prior art in that no peptides containing the non-naturally occurring amino acid D-Tic at the 7-position have been previously described.

The invention therefore relates to a process for the preparation of a therapeutically useful bradykinin antagonist of the formula I

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

* • where A is ax) hydrogen, acetyl, propionyl or methyloxycarbonyl in which one hydrogen atom is optionally replaced by carboxy, phenyl or 4-hydroxyphenyl, a2) carbamoyl optionally substituted • nitrogen-associated phenyl, phenylsulphonyl optionally substituted substituted with 1 or 4 groups of methyl and methoxy or pyridylcarbonyl, or 35 94353 2 a3) a group of formula II

R1 - N - CH - C - II

k 2 k 3 o 5 wherein R 1 is as defined in A in ax a) or a 2), R 2 is hydrogen, R 3 is (C 1 -C *) alkyl optionally monosubstituted with amino, substituted guanidine or 4-hydroxy-10-phenylphenyl, wherein the substituted guanidino is a group -NH-C (NH) -NH-A, wherein A is as defined in a :); B is Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homoarginine group, wherein the amino or guan-diine group of the side chain may be substituted by A as described in ai) or a2); C is a compound of formula IIIa or IIIb G'-G '-Gly IIIa G' -NH- (CH-) -CO IIIb wherein the G 'are independently groups of formula IV

R R O IV

I! "

.25 - N - CH - C

wherein R 4 and R 5 together with the atoms to which they are attached form a heterocyclic mono-, di- or tricyclic ring system of 2 to 15 C atoms and n is 2 to 8; . E is a phenylalanine group optionally substituted by halogen in the 2-, 3- or 4-position, tyrosine, O-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine; 35 94353 3 F is Ser, Hser, Lys, Leu, Val, Nle, Ile Thr or is a direct bond; (D) -Tic is a group of formula V;

YEAH

O H

G is as defined above G 'or is a direct bond; F 'is a basic amino acid group Arg or Lys in L- or D-form or a direct bond, wherein the guanidino or amino group of the side chain may be substituted by A as defined in a2) or a2), or is a group -NH- (CH2 ) n-, wherein n is 2 to 8, I is -OH, -NH2 or -NHC2H5, K is a group -NH- (CH2) x -CO-, where x = 1 to 4, or a direct bond, and M is like F, and for the preparation of its physiologically acceptable salts.

20 Unless otherwise stated, the abbreviation for amino acid ester without stereo explanation refers to the L-form group (cf. Schröder, Liibke, The Peptides, Part I, New York 1965, pp. XXII-XXIII; Houben-Weyl, Methoden der Organischen Chemie, Part XV / 1 and 2, Stuttgart 1974), such as .25 Aad, Abu, rAbu, ABz, 2ABz, 6Aca, Ach, Acp, Adpd, Ahb, Aib, * BAib, Ala, 8Ala, AAla, Alg, All, Ama, Amt, Ape, Apm, Apr,

Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys,

Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Dj en, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, HAla, hArg, hCys, hGln, hGlu, 30 His, hile, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp,. hTyr, Hyi, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Len, Leu,

Lsg, Lys, fiLys, ALys, Met, Mim, Min, nArg, Nle, Nva, Oly,

Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, ΔΡγο, Pse, Pya,

Pyr, Pza, Qin, Ros, Sar, See, Sem, Ser, Thi, BThi, Thr, 3Γ> Thy, Thx, Tia, Tie, Tly, Trp, Trta, Tyr, Vai.

94353 4

Suitable heterocyclic ring system groups of the formula IV are, in particular, the following group of heterocyclic groups: pyrrolidine (A); piperidine (B); tetrahydroisoquinoline 5 (C); decahydroisoquinoline (D); octahydroindole (E); octahydrocyclopenta [b] pyrrole (F); 2-azabicyclo [2.2.2] octane (G); 2-azabicyclo [2.2.1] heptane (H); 2-azaspiro [4.5] decane (I); 2-azaspiro [4.4] nonane (J); spiro [(bicyclo [2.2.1] heptane) -2,3-pyrrolidine] (K); spiro [(bicyclo [10.2] octane) -2,3-pyrrolidine] (L); 2-azatricyclo- [4.3.0.16 · 9] decane (M); decahydrocyclohepta [b] pyrrole (N); octahydroisoindole (O); Octahydrocyclopenta [c] pyrrole (P); 2,3,3a, 4,5,7a-hexahydroindole (Q); tetrahydrothiazole (R); 2-azabicyclo [3.1.0] hexane (S); isoxazolidine 15 (T); pyrazolidine (U); hydroxyproline (V); which you get in ways all of which may be substituted.

: 94353 5 = Q ~ 0 - “- OCT · 'Cfc-' · <* - 'g> -'

10 B »'P

e X £.

Ν ^ ° · 0 · εο "15 · η 'i 1 £' &„ <2ξ> ~ Q> - <o · »- * 1 LIM 1 N 1 1 /”) O. r— *: 25 V __ / B -Λ - (“Η Λ) —v S ^ * \ (~ \ co- ^) -co- | _ ^ Veo- 1 o 1 t 8 1 £. 1 * H0 \ 0-c ° - O-c0- 0-c ° 4 Ä 2 94353 6

The heterocycles underlying the above groups are known, for example, from U.S. Pat. No. 4,344,949, U.S. Pat. No. 4,374,847, U.S. Pat. No. 4,350,704, EP 50,800, EP 31,741, EP 51,020, EP 49,658, EP -49 605, EP-29 488, 5 EP-46 953, EP-52 870, EP-271 865, DE-32 26 768, DE-31 51 690, DE-32 10 496, DE-32 11 397, DE -32 11 676, DE-32 27 055, DE-32 42 151, DE-32 46 503 and DE-32 46 757.

Further, some of these heterocycles are disclosed in DE-38 18 850.3.

Unless otherwise indicated in individual cases, alkyl may be straight-chain or branched.

Halogen is fluorine, chlorine, bromine or iodine, preferably chlorine.

Suitable salts are, in particular, alkali or alkaline earth metal salts, salts with physiologically acceptable amines and salts with inorganic or organic acids such as HCl, HBr, H2SO4, H3PO4, maleic acid, fumaric acid, citric acid, tartaric acid, acetic acid.

Preferred are peptides of formula I wherein K is a group -NH- (CH 2) x -CO- where x = 2-4, or a direct bond.

Particularly preferred are peptides of formula I wherein • .25 B is Arg, Orn or Lys, wherein the guanidine group or amino group of the side chain is unsubstituted or substituted by 4-hydroxyphenylpropionyl, pyridylcarbonyl or phenylsulfonyl, where the phenylsulfonyl group may be optionally substituted at the 2-position. 30 in an incomplete manner with 1 or 4 of the same or different groups; E is phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenyl-55-alalanine, tyrosine, O-methyltyrosine or B- (2-thienyl); 94353 7 K is a direct bond; and M is a direct bond.

Very particularly preferred are the peptides of the formula I in which A is hydrogen, (D) - or (L) -H-Arg, (D) - or (L) -H-Lys or (D) - or (L) - H-Orn; B is Arg, Orn or Lys, wherein the amino group of the side chain may be substituted by hydrogen, 4-hydroxyphenylpropionyl, pyridylcarbonyl or phenylsulfonyl, wherein the phenylsulfonyl group may be optionally substituted by 1 or 4 identical or different groups selected from methyl and methoxy; C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly; E is Phe or Thia; F is Ser, Hser, Lys, Leu, Val, Nle, Ile or Thr; K is a direct bond; M is a direct bond; G is a heterocyclic ring system group of formula IV, wherein the heterocyclic groups are preferably pyrrolidine (A); piperidine (B); tetrahydroisoquinoline (C); cis- or trans-decahydroisoquinoline (D); cis-endo-octahydroindole (E), cis-el: so-octahydroindole (E), trans-octahydroindole (E), cis-endo-, cis-exo-, or trans-octahydrocyclopentano [b] pyrrole (F); or hydroxy- • • 25 proline (V); F 'is Arg; and I is OH.

Examples of very particularly preferred peptides of the 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-Phe- 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 process according to the invention for the preparation of peptides of the formula I is characterized in that 94353 8 a) a part having a free C-terminal carboxyl group or an activated derivative thereof is reacted with a corresponding part having a free N-terminal amino group, or 5 b) the peptide is constructed stepwise according to a solid phase method, the compound obtained according to (a) or (b) is optionally cleaved with one or more protecting groups 10 temporarily attached to protect other functional groups and the compounds of formula I thus obtained are optionally modified with physiologically acceptable in the form of salts.

The peptides of this invention were prepared according to generally known methods of peptide chemistry, see for example Hoyben-Weyl, Methoden der organischen Chemie, Part 15/2, preferably by solid phase synthesis such as B. Merrifield, J. Am. Chem. Soc. 85 (1963) pp. 2149, or R. C. Sheppard, Int. J. Peptide Protein Res. 21 (1983) p. 118, or by similar known methods. As the α-amino protecting groups, urethane protecting groups such as tert-butyloxycarbonyl (Boc) or fluorenylmethyloxycarbonyl (Fmoc) protecting groups were used. If required to prevent side reactions or to synthesize specific peptides, the functional groups of the amino acid side chains were protected with appropriate protecting groups (see, e.g., TW Greene, "Protective Groups in Organic Synthesis"), with Arg (Tos), Arg (Mts. ), Arg (Mtr), Arg (PMC), Asp (OBzl), Asp (OBut), Cys (4-MeBzl), Cys (Acm), Cys (SBut), Glu (OBzl), Glu (OBut), Ηχεί Tos), His (Fmoc), His (Dnp), His (Trt), Lys (Cl-Z), Lys (Boc), 30 Met (O), Ser (Bzl), Ser (But), Thr (Bzl) , Thr (But), Trp (Mts), Trp (CHO), Tyr (Br-Z), Tyr (Bzl) or Tyr (But).

Solid phase synthesis is initiated by the incorporation of an amino acid protected from the C-terminus of the peptide into the corresponding resin. Such starting materials can be obtained by combining a protected amino acid with a chloromethyl, hydroxymethyl, benzhydrylamino (BHA) or methylbenzhydryl amino (MBHA) group modified polystyrene or polyacrylamide resin with an ester or amide bond. Resins used as media are commercially available. If the peptide is to contain a secondary amide group at the C-terminus, a chloromethyl or hydroxymethyl resin is used and cleavage is performed with the corresponding amines. If it is desired to preserve ethylamide, the peptide can be cleaved from the resin with ethylamine, with cleavage of the side chain protecting groups in the future by other suitable reagents. If the tert-butyl protecting groups of the amino acid side chain are to be retained in the peptide, the synthesis is performed with an Fmoc protecting group to temporarily protect the α-amino group of the amino acid, e.g., R.C. Shep-pardin, J. Chem. Soc., Chem. Comm. 1982, p. 587, describe in a manner in which the guanidine group of arginine is protected by protonation with pyridinium perchlorate and the protection of other amino acids with side chains is effected by catalytic deprotection (A. Felix et al., J. Org. Chem. 13 (1988), p. 4194). ) or benzyl protecting groups which can be cleaved with sodium in liquid nitrogen (W. Roberts, J. Am. Chem. Soc. 76 (1954), p. 6203).

After cleavage of the amino protecting groups of the amino acids attached to the resin with a suitable reagent such as trifluoroacetic acid in methylene chloride for the Boc protecting group or a 20% solution of piperidine in dimethylformamide for the Fmoc protecting group, the following protected amino acids are sequentially added as desired. The N-terminally protected peptide resins formed as intermediates are protected with the reagents described above before coupling with the next amino acid derivative.

Suitable coupling reagents are all activating reagents used in peptide synthesis, see for example Houben-Weyl, Methoden der organischen Chemie, Part 15/2, but in particular carbodiimides such as, for example, N, N'-dicyclohexylcarbodiimide, Ν, Ν '-diisopropylcarbodiimide or N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide. The coupling to the resin can then be carried out directly by the addition of an amino acid derivative Akti-5 lubricating reagent and possibly an anti-racemizing additive such as 1-hydroxybenzotriate-Sol (HOBt) (W. König and R. Geiger, Chem. Ber. 103 (1970), p. 708) or With 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) (W. König and R. Geiger, Chem. Ber. 103 10 (1970), p. 2054) but the amino acid derivative can be preactivated to a symmetrical anhydride or HOBt or HOObt ester separately and add a solution of the activated species in a suitable solvent to the coupling peptide-resin.

Coupling or activation of an amino acid derivative of any of the above activating reagents may be performed in dimethylformamide, N-methylpyrrolidone or methylene chloride or a mixture of said solvents. The activated amino acid derivative is usually used in a 1.5- to 4-fold excess. In cases where incomplete coupling occurs, the coupling is repeated without performing the deprotection of the α-amino group of the peptide resin required for the coupling of the next amino acid.

The success of the coupling reaction can be tested by the nin-J25 hydrin reaction, such as E. Kaiser et al. Anal. Biochem. 34 (1970) p. 595, describes. The synthesis can also be automated, for example, with a peptide synthesizer model 430A, Applied Biosystems, in which case either the synthesis programs provided by the device manufacturer, but also the device's own synthesis programs can be used. Last-·. said are used in particular when using amino acid derivatives protected by Fmoc groups.

Following peptide synthesis, as described above, the peptide can be cleaved from the resin with reagents such as, for example, liquid hydrogen fluoride (preferably a peptide prepared by the Boc method) or trifluoroacetic acid (preferably peptides prepared by the Fmoc method). These reagents not only cleave the peptide from the resin but also other side chain protecting groups of amino acid derivatives. In this way, in addition to BHA and MBHA resins, the peptide is obtained in the form of the free acid.

BHA or MBHA resins are obtained by cleavage of the peptide as an acid amide with hydrogen fluoride or trifluoromethanesulfonic acid. Other methods for preparing peptide amides are described in patent applications DE-37 11 866.8 and DE-37 43 620.1. In these, the cleavage of the peptide amide from the resin is accomplished by treatment with moderate acids (e.g., trifluoroacetic acid) conventionally used in peptide synthesis using cationic scavengers such as phenol, cresol, thiocresol, aniseolide azide sulfide, anisole, thioanisole, ethanedithiolide, ethanedithiolide, or as a mixture of more than one of these excipients. Trifluoroacetic acid can then also be diluted with suitable solvents such as methylene chloride.

If the tert-butyl or benzyl protecting groups of the peptide side chain are to be preserved, in particular, the peptide synthesized with the modified medium resin is cleaved with 1% trifluoroacetic acid with methylene chloride, as described, for example, by R.C. Sheppard, J. Chem. Soc., 'J25 Chem. Commun. 1982, p. 587. If individual tert-butyl or benzyl protecting groups on the side chains are to be retained, a suitable combination of synthetic and cleavage methods is used.

To synthesize peptides having a C-terminal amide group or a β-amino or β-guanidinoalkyl group, a modified medium resin as described by Sheppard is likewise used. After synthesis, the peptide fully protected from the side chains is cleaved from the resin and finally reacted by classical solution synthesis (Lösungs-35 Synthese) with the corresponding amine or U-aminoalkylamine or N-guanidinoalkylamine, whereby any other functional groups present can be temporarily protected in a known manner.

A further method for the preparation of peptides containing a--aminoalkyl group is described in patent application DE-36 35 670.0.

The peptides described herein were synthesized primarily using the solid phase technique according to two general protecting group tactics:

The synthesis was performed on an automated peptide synthesizer-Model 430A, Applied Biosystems, using Boc or Fmoc protecting groups for temporary protection of α-amino groups.

When using Boc protecting groups, the synthesis cycles pre-programmed by the device manufacturer were utilized in the synthesis.

The synthesis of peptides containing free carboxyl groups at the C-terminus was performed with the corresponding Boc amino acid-functionalized 4- (hydroxymethyl) phenylacetamidomethylpolystyrene-20-reene resin from Applied Biosystems [R.B. Merrifield, J. Org. Chem. 43 (1978), p. 2845]. MBHA resin from the same company was used to prepare the peptide amides.

N, N'-dicyclohexylcarbodiimide or N, N'-diisopropylcarbodiimide was used as activating reagents. Activation took place as a symmetrical anhydride, HOBt ester or HOObt ester in CH2Cl2, CH2Cl2 / DMF or MNPr. 2-4 equivalents of activated amino acid derivative were used for coupling. If the coupling was incomplete, the reaction was repeated.

When using Fmoc protecting groups for temporary protection, the Model 430A, Applied Biosystems, proprietary synthesis program, was used for synthesis on an automated peptide synthesizer. The synthesis took place with p-Benzyloxybenzyl alcohol resin from Bachem (S. Wang, J. Am. Chem. 35 Soc. 95 (1973) p. 1328), which was esterified by a known method (E. Atherton et al., JCS Chem. Comm. 1981 li 13 94353 p. 336) with the corresponding amino acid. Activation of the amino acid derivative as HOBt or HOObt ester occurred directly in the amino acid cassettes supplied by the device manufacturer by adding a solution of diisopropylcarbodiimide in DMF to a mixture of pre-weighed amino acid derivative and 5 HOBt or H00bt. Similarly, the Fmoc amino acid OObt ester prepared in the medium could be used as described in patent application EP-87107634.5. Cleavage of the Fmoc protecting group was performed with 20% piperidine / DMF solution in a reaction vessel. The excess of reactive amino acid derivative used was 1.5 to 2.5 equivalents. If the coupling was not complete, it was repeated by the Boc method.

The peptides of the invention, alone or in combination, have an opposite effect to bradykinin, which can be tested in various models (see Handbook of Exp. Pharmacol. Part 25, Springer Verlag, 1970, pp. 53-55), for example in isolated rat uterus, guinea pig ileum or isolated guinea pig pulmonary; molla.

In the pulmonary arteries isolated for testing peptides prepared according to the invention, guinea pigs weighing 400 to 450 g (Dunkin Hartley) were killed by neck stroke.

The thorax was opened and the pulmonary artery was carefully exposed. The surrounding tissue was carefully removed and the pulmonary artery was incised in a helical angle at a 45 ° angle.

A 2.5 cm long and 3-4 mm wide vascular strip was attached to an organ bath filled with 10 ml of Ringer's solution. Composition of the solution, mmol / l NaCl 154 30 KCl 5.6

CaCl2 1.9

NaHCO 3 2.4 glucose 5.0

The solution was aerated with 95% and 5% CO 2 and warmed to 37 ° C. The pH was 7.4, the initial load applied to the vascular strips was 1.0 g.

94353 14

Isotonic contraction changes were taken with a Hugo Sachs lever and HF modem (distance meter) and recorded with an equalizer (BEC, Goerz Metrawatt SE 460).

5 Experiments were started after 1 hour of equilibration. When the vascular strips had reached their maximum sensitivity to 2 x 10'7 mol / l bradykinin - bradykinin leads to contraction of the vascular strips - the peptides were allowed to act in doses of 5 x 10 * 8 to 1 x 10'5 10 mol / l in each case and compared with the regenerated bradykinin dose. after the effect of bradykinin compared to control.

To identify a partial opposite effect, peptides were used at a dose of 1 x 10 * 5 to 1 x 10 "3 mol / l.

The IC50 values of the peptides prepared according to the invention obtained from the dose / response curves are shown in Table 1.

Table 1 • 20 Compound IC50 [M] H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic- 4.6 · 10 * 6

Phe-Arg-OH

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic- 2.1 · 10'6

Thia-Arg-OH

• 2b H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tie- 1,2 · 10 * 5

Phe-Arg-OH

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Glo- (D) -Tie- 2,4 · 10’5

Phe-Arg-OH

H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic- 2.5 · 10 ~ 5

30 Phe-Arg (Mtr) -OH

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic- 2.5 ♦ 10'7

Pro-Arg-OH

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic- 1.9 ♦ 10 "7

Pro-Arg-OH

35 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic- 5.6 · 10-8

AOC ^ rg-OH

94353 15 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-8-Ala- 1,7 · ΙΟ'6

(D) -Tic-Aoc-Arg-OH

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- 3.9 · 10'7

(D) -Tic-Aoc-Arg-OH

5 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D) -Tic- 3.2 · 10'7

(D, L) -Oic-Arg-OH

H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) - 4.8 · 10'7

Tic-Aoc-Arg-OH

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic- 1.7 · 10'7

10 Tic-Arg-OH

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic- 1,1 · 10'8

Aoc-Arg-OH

H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic- 4.6 · 10'8

Aoc-Arg-OH

15 H- (D) -Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic- 6.2 · 10'8

Aoc-Arg-OH

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic- 2,6 · 10'5

(D) -OiC-Arg-OH

: H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic- 5.4 · 10'9 «

20 Oic-Arg-OH

H- (D) -Arg-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic- 3.2 · 10'7

Aoc-Arg-OH

H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic- 6.8 · 10'9

Oic-Arg-OH

• 25 H- (D) -Arg-Arg- (NO2) -Pro-Hyp-Gly-Phe-Ser- (D) - 6.4 · 10 ~ 8

Tic-Aoc-Arg-OH

H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic- 4.2 · 10'9

Oic-Arg-OH

H- (D) -Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic- 3,4 · 10'7

30 Arg-OH

H-Arg- (Tos) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic- 3.0 · 10'8

Dic-Arg-OH

H-Arg- (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic- 1.8 · 10'8

Dic-Arg-OH

Therapeutic utilization of the peptides of the invention encompasses all conditions mediated, induced and maintained by bradykinin or 94353 16 bradykinin-related peptides. These include, but are not limited to, lesions such as wounds, burns, rashes, erythema, hydrocephalus, sore throat, arthritis, asthma, allergy, rhinitis, shock, inflammation, hypotension, pain, scabies, and impaired sperm.

Pharmaceutical preparations containing these compounds contain an effective amount of a drug of formula I - alone or in combination - together with an inorganic or organic pharmaceutically acceptable medium.

The administration can take place enterally, parenterally - such as subcutaneously, intramuscularly or intravenously -, sublingually, on the skin, nose, anus, vagina, cheek or by inhalation. The dosage of the drug depends on the species, body weight, age and route of administration of the warm-blooded animal.

Suitable dosage ranges for topical and inhaled forms include solutions containing 0.01 to 5 mg / ml, and for systemic administration forms suitable doses are 0.01 to 10 mg / kg.

Explanations of Abbreviations The abbreviations used for amino acids correspond to the three-letter symbols commonly used in peptide chemistry in Europ. J. Biochem. 138 (1984) p. 9. The other abbreviations used are listed below. Acm acetamidomethyl 30-Ahx 6-aminohexanoyl. Aoc cis, endo-2-azabicyclo [3.3.0] octane-3-S-carbonyl

Boc tert-butyloxycarbonyl

But tert-butyl 35 Bzl benzyl

Cl-Z 4-chlorobenzyloxycarbonyl 94353 17 DMF dimethylformamide

Dnp 2,4-dinitrophenyl

Fmoc 9-fluorenylmethyloxycarbonyl

Me methyl 5-Mebzl 4-methylbenzyl

Mt.r 4-Methoxy-2,3,6-trimethylphenylsulfonyl

Mts mesitylene-2-sulfonyl NMP N-methylpyrrolidine

Oic ci s-endo-octahydroindole-2-carbonyl 10 Opr isoxazolidin-3-ylcarbonyl

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl TFA trifluoroacetic acid

Tcs 4-methylphenylsulfonyl

Thia 2-thienyl ± alanyl 15 Tic 1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl

Trt trityl

The following examples illustrate preferred methods for solid phase synthesis of peptides in accordance with the invention.

* 20 The following amino acid derivatives were used:

Fmoc-Arg (Mtr) -OH, Boc- (D) -Arg-OH, Fmoc-Arg (Pmc) -OH, Fmoc-Hyp-OH, Fmoc-Pro-00bt, Fmoc-Gly-OObt, Fmoc-Phe- OObt, Fmoc-Ser (tBu) -00bt, Fmoc- (D) -Tic-OH, Fmoc-Gln-OH, Fmoc-Aoc-OH, Fmoc-Thia-OH, Fmoc-Opr-OH, Fmoc- (D) -Asn-OH, Fmoc-B-Ala-25 OH, Fmoc-O-O-OH.

Example 1 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH was prepared stepwise on a Model 430 A peptide synthesizer, Applied Biosystems, using Fmoc method 30 With p-benzyloxybenzyl alcohol resin esterified with Fmoc-Arg (Mtr) -OH from Novabiochem (loading • · about 0.5 mmol / g resin). 1 g of resin was used and the synthesis was performed using a synthesis program modified for the Fmoc method.

In each case, 1 mmol of amino acid derivatives containing free carboxyl groups together with 0.95 mmol of H00bt were weighed into the synthesizer cassettes. The preactivation of these amino acids took place directly in the cassettes by dissolving in 4 ml of DMF and adding 2 ml of a 0.55 mol solution of diisopropylcarbodiimide in DMF. The 5 HOObt esters of the other amino acids were dissolved in 6 mL of NMP and then pre-coupled with 20% piperidine / DMF to the deprotected resin as well as the in situ preactivated amino acids. After completion of the synthesis, the peptide was cleaved from the resin by simultaneous deprotection of the side chains with trifluoroacetic acid using thioanisole or ethanedithiol as a cation scavenger. After removal of trifluoroacetic acid, the residue obtained was extracted several times with ethyl acetate and centrifuged. The remaining residue was chromatographed on ®Sephadex LH 20 with 10% acetic acid. The fractions containing pure peptide were combined and lyophilized.

MS (FAB): 1294 (M + H)

The peptides of the following Examples 2-24 were prepared and purified in the same manner.

* 20 Example 2 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe- (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-25 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-Gln- (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) 35 Example 7 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Trp- (D) -Tic-Phe-Arg-OH, MS (FAB): 1393 (M + H) 94353 19

Example 8 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH, MS (FAB): 1250 (M + H)

Example 9 5 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Asn- (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) 10 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-15 Arg-OH, 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-S-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): 1220 (M + H)

Example 17 H - (D) -Arg-Arg-Aoc-Pro-Gly-Thia-Ser- (D) -Tic-Thia-30 Arg-OH, MS (FAB): 1330 (M + H)

Example 18 t ♦ 1 H- (D) -Arg-Arg-Pro-Aoc-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH, MS (FAB): 1330 (M + H)

Example 19 35 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1290 (M + H) 94353 20

Example 20 H- (D) -Arg-Arg-Opr-Pro-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): 1252 (M + H) 10 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-15 OH, MS (FAB): 1290 (M + H)

Examples 25-27 H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-

Arg-OH, 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 were prepared according to Example 1. in a manner in which the cleavage of the side chain protecting groups and the cleavage of the peptide from the resin by trifluoroacetic acid were limited to 30 minutes at room temperature. Under the conditions thus selected, only non-existent cleavage of the Mtr protecting groups of Arginine occurs. Peptides partially deprotected can be separated and purified by reverse phase material chromatography.

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

Arg-OH, MS (FAB): 1506 (M + H) 26 26: H- (D) -Arg-Arg (Mtr) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-

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)

The peptides of the following Examples 28-31 were prepared and purified as in Examples 25-27.

94353 21

Example 28 H- (D) -Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH, MS (FAB): 1462 (M + H)

Example 29 5 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) 10 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- (CH2) 4-NH2. Peptide synthesis was performed on 1 g of aminoethyl resin modified with the attachment group described in EP-264 802 as Cmc-NH- (CH2) 4-NH-CO-O-CH2-C'C- O-CH 2 -C0- ^ ^ c-cr using Fmoc amino acid OObt esters with an automated peptide synthesizer (Model 430A, Applied Biosystems-25) and a self-modified synthesis program. To this end, 1 mmol of the corresponding amino acid derivative was weighed in each case into the cassettes supplied by the device manufacturer, Fmoc-Arg (Mtr) -OH, Fmoc-Hyp-OH and Fmoc- (D) -Tic-OH were weighed together with 0.95 mmol of HOObtr. In situ preactivation of these 30 amino acids occurred directly in the cassettes by dissolving in 4 ml of DMF and adding 2 ml of a 0.55 M solution of diisopropylcarbodiimide in DMF. The HOObt esters of the other amino acids were dissolved in 6 mL of NMP and and then coupled with a 20% piperidine / DMF deprotected resin as well as the in situ preactivated amino acids to give in situ activated amino acids. became connected twice. After completion of the synthesis, the peptide-4-aminobutylamide was cleaved from the resin by simultaneous deprotection of the side chains with trifluoroacetic acid containing thioanisole and 5 m-cresol as a cation scavenger. After removal of trifluoroacetic acid, the residue obtained was extracted several times with ethyl acetate and centrifuged. The remaining crude peptide was chromatographed on ®Sephadex G25 with 1 N acetic acid. The fractions containing pure peptide were combined and lyophilized.

The compounds of Examples 33-35 were prepared as in Example 32:

Example 33 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH-15 (CH2) 4-NH2.

Example 34 HOOC- (CH2) 2-CO-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH2) 4-NH2.

Example 35 '20 HOOC- (CH2) 2-CO- (D) -Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-

Phe-NH- (CH2) 4-NH2.

The peptides of Examples 36-161 were prepared as 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-

I I

OH, MS (FAB): 1241 (M + H)

Example 39 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser-S-Ala- (D) -Tic-35 Aoc-Arg-OH, MS (FAB): 1361 (M + H) 94353 23

Example 40 H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser-β-Ala- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1361 (M + H)

Example 41 5 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) 10 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-15 OH, MS (FAB): 1260 (M + H)

Example 45 H- (D) -Arg- (D) -Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1290 (M + H)

Example 46 '20 H- (D) -Arg- (D) -Arg-Pro-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) 25 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-30 OH, MS (FAB): 1274 (M + H)

Example 50 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1203 (M + H)

Example 51 35 H- (D) -Arg-Arg-Hyp-Pro-Gly-Aoc-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1274 (M + H) 94353 24

Example 52 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-B-Ala- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1274 (M + H)

Example 53 5 H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-B-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) 10 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-15 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 20 H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic- (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) Example 60 H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oio-Arg-OH, MS (FAB): 1289 (M + H)

Example 61 H- (D) -Arg-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-30 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 35 H- (D) -Arg-Lys-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1260 (M + H) 94353 25

Example 64 H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1298 (M + H)

Example 65 5 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) 10 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-15 Arg-OH, MS (FAB): 1343 (M + H)

Example 69 H- (D) -Arg-Arg (NO 2) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (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): 1349 (M + H) Example 72 H-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1302 (M + H)

Example 73 H- (D) -Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, 30 MS (FAB): 1142 (M + H)

Example 74 * n-s-Ly s (-CO-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1233 (M + H )

Example 75 35 H-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1296 (M + H) 26 94355

Example 76 H-Lys (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1219 (M + H)

Example 77 5 H-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) 10 Example 79 H- (D) -Arg -Arg (Tos) - Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1438 (M + H)

Example 80 H-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-15 OH, MS (FAB): 1302 (M + H)

Example 81 H-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1142 (M + H) ': Example 82 t ~' - 20 H- Lys (-CO-NH-C6H5) -Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-

Arg-OH, MS (FAB): 1233 (M + H)

Example 83 H-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1296 (M + H) 25 Example 84 H-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, 30 MS (FAB): 1282 (M + H)

Example 86

Ac-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1324 (M + H)

Example 87 35 H- (D) -Arg-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Aoc-

Arg-OH, MS (FAB): 1438 (M + H) 94353 27

Example 88 H-Arg (Tos) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1286 (M + H)

Example 89 5 H-Arg-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1126 (M + H)

Example 90 H-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1217 (M + H) 10 Example 91 H-Arg (Tos) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1280 (M + H)

Example 92 H-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-15 OiC-Arg-OH, MS (FAB): 1203 (M + H)

Example 93 H-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 H- (D) -Arg-Arg (Tos) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1422 (M + H) Example 96 H-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1148 (M + H)

Example 97 H-Lys (-C0-NH-C6H5) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-30 Arg-OH, MS (FAB): 1239 (M + H)

Example 98% I '' H-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-

Oic-Arg-OH, MS (FAB): 1225 (M + H)

Example 99 35 H-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1288 (M + H) 94353 28

Example 100

Ac-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1330 (M + H)

Example 101 5 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-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1148 (M + H) 10 Example 103 H-Lys (-CO-NH -C6H5) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1239 (M + H)

Example 104 H-Lys (nicotinoyl) -Hyp-Pro-Gly-Thia-Ser- (D) -Tic-15 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): 1288 (M + H)

Example 106 * * 20 Ac-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser- (D) -Tie-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) .25 Example 108 H-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1225 (M + H)

Example 109 H-Lys (nicotinoyl) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-30 Oic-Arg-OH, MS (FAB): 1209 (M + H). Example 110 H-Arg (Tos) -Pro-Pro-Gly-Thia-Ser- (D) -Tie-Aoc-Arg-OH, MS (FAB): 1272 (M + H)

Example 111 35 Ac-Arg (Tos) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1314 (M + H) 94353 29

Example 112 H- (D) -Arg-Arg (Tos) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH, MS (FAB): 1428 (M + H)

Example 113 5 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 (-CO-NH-C6H5) -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 + B)

Example 116 H-Lys-Lys (nicotinoyl) -Pro-Pro-Gly-Thia-Ser- (D) -15 Tic-Oic-Arg-OH, MS (FAB): 1337 (M + H)

Example 117 H-Lys-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1351 (M + H)

Example 118 '20 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) -Tic-Oic-Arg-OH, MS (FAB): 1381 (M + H) 25 Example 120 • - H- (D) -Arg-Lys (C0-NH-C6H5) -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-30 0ic-Arg-OH, MS (FAB): 1458 (M + H). Example 122 H-Lys-Lys (-C0-NH-C6H5) -Pro-Hyp-Gly-Thia-Ser- (D 2 Tic-Oic-Arg-OH, MS (FAB): 1367 (M + H)

Example 123 35 H-Lys-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser- (D) -

Tic-Oic-Arg-OH, MS (FAB): 1353 (M + H) 94353 30

Example 124 H-Lys-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1430 (M + H)

Example 125 5 H- (D) -Arg-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1359 (M + H)

Example 126 H- (D) -Arg-Lys (-CO-NH-C6H5) -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 + B)

Example 128 H-Lys-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser- (D) -15 Tic-Oic-Arg-OH, MS (FAB): 1331 (M + H)

Example 129 H-Lys-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1345 (M + H)

Example 13020 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 (FAB): 1375 (M + H) 25 Example 132 H- (D) -Arg-Lys (-C0-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1389 (M + B)

Example 133 H- (D) -Arg-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-30 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 35 H-Lys-Lys (-C0-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-

Oic-Arg-OH, MS (FAB): 1361 (M + H) 94353 31

Example 136 H-Lys-Arg (Tos) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1424 (M + H)

Example 137 5 H- (D) -Arg-Orn (nicotinoyl) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1351 (M + H)

Example 138 H- (D) -Arg-Orn (-CO-NH-C6H5) -Pro-Pro-Gly-Thia-Ser- (Π) -Tic-Oic-Arg-OH, MS (FAB): 1428 (M + H) Example 139 H-Lys-Orn (nicotinoyl) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1323 (M + H)

Example 140 H-Lys-Orn (-CO-NH-C6H5) -Pro-Pro-Gly-Thia-Ser- (D) -Tic-150 O-Arg-OH, MS (FAB): 1337 (M + H)

Example 141 H- (D) -Arg-Orn (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1367 (M + H)

Example 142 * 2C H- (D) -Arg-Orn (-CO-NH-C6H5) -Pro-Hyp-Gly-Thia-Ser- (D) -

Tic-Oic-Arg-OH, MS (FAB): 1381 (M + H)

Example 143 H-Lys-Orn (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1339 (M + H) .25 Example 144 H- Lys-Orn (-CO-NH-C6H5) -Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1353 (M + H)

Example 145 H- (D) -Arg-Orn (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-30 (D) -Tic-Oic-Arg-OH, MS (FAB): 1345 (M + H). Example 146 H- (D) -Arg-Orn (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1359 ( M + H)

Example 147 35 H-Lys-Orn (nicotinoyl) -Pro-Pro-Gly-Phe-Ser- (D) -

Tic-Oic-Arg-OH, MS (FAB): 1317 (M + H) 94353 32

Example 148 H-Lys-Orn (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1331 (M + H)

Example 149 5 H- (D) -Arg-Orn (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1361 (M + H)

Example 150 H- (D) -Arg-Orn (CO-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, M3 (FAB): 1375 (M + H) Example 151 H-Lys-Orn (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1333 (M + H)

Example 152 H-Lys-Orn (-CO-NH-C6H5) -Pro-Hyp-Gly-Phe-Ser- (D) -Tic-15 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 2C 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) • 25 Example 156 1 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, 30 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 35 H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1248 (M + H) 94353 33

Example 160 H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1226 (M + H)

Example 161 5 H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, MS (FAB): 1242 (M + H)

The peptides of Examples 162-164 were prepared as in Example 32 using a resin having the structure described in EP-322348.

F mec-NH OCH3 I

15 CH2 C-0

NH

CHp SO (Polystyrene)

Example 162 H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-NH 2, MS (FAB): 1283 (M + H) 25 Example 163 • 1 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-3er- (D) -Tic-Aoc-Arg-NH 2, MS (FAB): 1283 (M + H)

Example 164 H- (D) -Arg-Arg-Pro-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-30 NH 2, MS (FAB): 1267 (M + H) • · 4

Claims (9)

A process for the preparation of a therapeutically useful bradykinin antagonist of formula I ABCEFK- (D) -Tic-GM-F'-II wherein A is ax) hydrogen, acetyl, propionyl or methyloxycarbonyl, wherein a hydrogen atom is optionally replaced by carboxy, phenyl or 4-hydroxyphenyl, a2) carbamoyl optionally substituted at the nitrogen atom by phenyl, phenylsulfonyl optionally substituted by 1 or 4 groups of methyl and methoxy, or pyridylcarbonyl, or a3) a group of formula II R 1 - N Wherein R 1 is as defined in A (a) a) or a 2), R 2 is hydrogen, R 3 is (C 1 -C 3 alkyl optionally mono-substituted with amino, substituted guanidino or hydroxyphenyl, wherein the substituted guanidinone is a compound * -NH-C (NH) -NH-A, where A is as defined in point ai); B is Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homoarginine group, wherein the side chain amino and guanidino group, respectively, can be substituted with A as indicated in point ax) or a2); . C is a compound of formula purple or IIIb in G'-G'-Gly G'-NH- (CH9) -CO M Π Ula Illb, wherein G 'is independently of groups of formula IV RRO IV 5 - λ - CH - C where R 4 and R 5 together with the atoms to which they are attached form a heterocyclic mono-di or tricyclic ring system having 2-15 C atoms and n is 2-8; E is a phenylalanine group optionally substituted with halogen ± 2-, 3- or 4-position, tyrosine, 0-methyl tyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine; F is Ser, Hser, Lys, Leu, Val, Nle, Ile Thr or a direct bond; (D) -Tic is a group of formula V; rf G is as defined above G 'or a direct bond; F * is a basic amino acid group Arg or Lys in L-2b or D form or a direct bond, wherein the side chain 1 guanidino and amino group, respectively, can be substituted with A as defined in points a2) or a2) or is a group -NH- (CH 2) n -, where n = 2 - 8, 1 is -OH, -NH 2 or -NHC 2 H 5, K is a group -NH- (CH2) x -CO-, where x * 1-4, or. a direct bond, and M is as F, and for the production of physiologically acceptable salts thereof, characterized in that a) a fragment having a free C-terminal carboxyl group or an activated derivative thereof reacts with a the corresponding fragment having a free N-terminal amino group, or b) constructing the peptide step by step according to the solid phase procedure, from the compound obtained according to (a) or (b), optionally cleaves one or more temporarily linked protecting groups for other functional groups and even In general, the well-obtained compounds of formula I convert into physiologically acceptable salt form. A process according to claim 1, characterized in that a compound wherein B is Arg, Orn or Lys is prepared, wherein the guanidino group and amino group respectively are unsubstituted or substituted by 4-hydroxyphenylpropionyl, pyridylcarbonyl or phenylsulfonyl. wherein the phenylsulfonyl group may be optionally substituted in point a2) as indicated by 1 or 4 equal or different groups; E is phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, O-methyltyrosine or β- (2-thienyl) alanine; and K is a direct bond; and 25 M is a direct bond. A process according to claim 1, characterized in that a compound wherein A is hydrogen, (D) - or (L) -H-Arg, (D) - or (L) -H-Lys or ( D) - or (L) -H-Orn; B is Arg, Orn or Lys, wherein the side chain guanidino group and amino group, respectively, may be substituted with * hydrogen, 4-hydroxyphenylpropionyl, pyridylcarbonyl or phenylsulfonyl, the phenylsulfonyl group optionally substituted with 1 or 4 equal or different groups among methyl and methoxy. ; C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly; E is Phe or Thia; F is Ser, Hser, Lys, Leu, Val, Nle, Ile or Thr; K is a direct bond; 5 M is a direct bond; G is a heterocyclic ring system of formula IV, wherein the heterocyclic groups are pyrrolidine (A); piperidine (B); tetrahydroisoquinoline (C); cis- or trans-decahydroisoquinoline (D); cis-endo-octahydroindole (E), cis-exo-octahydroindole (E), trans-octahydroindole (E), cis-endo, cis-exo-, or trans-octahydrocyclopentano- [b] pyrrole (F); or hydroxyproline (V); F 'is Arg; and you are OH. A process according to claim 1, characterized in that the compound H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, H is prepared. - (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH, H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser - (D) -Tic-Oic-Arg-OH, H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, or H- (D) -Arg-Arg-Pro-Pro-Gly- Phe-Ser- (D) -Tic-Oic-Arg-OH. Γ