LV10720B - Peptides and pharmaceutical composition containing them - 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

LV 10720

Description

Peptides having.bradykinin antagonist action

The invention relates to novel peptides having bradykinin 5 antagonist action and to a process for their preparation.

Bradykinin antagonist peptides are described in WO 86/07263 in which, inter alia, L-Pro in position 7 of the peptide hormone bradykinin or other bradykinin analogs is replaced by a D-amino acid, such as D-Phe, 10 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.

The invention is based on the object of finding novel active peptides having bradykinin antagonist action.

15 This object is achieved by the peptides of the formula I A-B-C-E-F-K- (D)-Tic-G-H-F'- I ' in which A ax) denotes hydrogen, (Cl-Ce)-alkyl, 20 (Cl-C8)-alkanoyl, (Cx-Ce) -alkoxycarbonyl or (Cx-C9) -alkylsulf onyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or 3 identical or different 25 radicals from the series comprising carboxyl/ amino, (Ci-C4)-alkyl/ (Ci-C*) -alkylamino, -30 hydroxyl, (Ci-C4)-alkoxy, halogen, di- (Cx-C4) -alkylaxnino, 2 carbamoyl, sulfamoyl, (Ci-C*) -alkoxycarbonyl, (C6-C12)-aryl and 5 (C6-C12)-aryl-(C1-Cs)-alkyl/ or in which in each case 1 hydrogen atom is optionally replaced by a radical from the series comprising (C3-C8) -cycloalkyl, (Cļ-C*) -alkylsulf onyl, 10 (C1-C4)-alkylsulfinyl, (C6-Ci2) -aryl-(Cļ-C*) -alkylsul f onyl, (C6—C12) -aryl- (C^C*) -alkylsulfinyl, (C6-C12)-aryloxy, (C3-Cg)-heteroaryl and 15 (C3-C9) -heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or dif£erent radicals from the series comprising carboxyl/ 2 0 amino, (Cl-Ck) -alkylamino, hydroxyl, (C1-C*)-alkoxy/ halogen, 25 di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (Ci-C*) -alkoxycarbonyl, (C6-C12)-aryl and 30 (C6-C12) -aryl- (Cx-Cs) -alkyl, a2) denotes (C3-C8)-cycloalkyl, carbamoyl, which may be optionally substituted on the nitrogen by (C1-C6)-alkyl or (C6-Cl2)-aryl, (C6-C12)-aryl# (C7-C13)-aryloyl/ (C6-C12) -arylsulf onyl, (C3-C9)-heteroaryl, or (C3-C9)-heteroaryloyl, where in the radicals defined under aj and a2) in each case aryl, heteroaryl, aryloyl, arylsulfonyl and 35 - 3 - - 3 - LV 10720 heteroaryloyl is optionally substituted by 1, 2, 3 or 4 identical or different radicals from the series cora-prising carboxyl, amino, nitro, (Cļ-C*) -alkylami.no, hydroxyl, (Ci-C*)-alkyl, (Cl-CJ-alkoxy/ halogen, cyano,

di-(C^C*)-alkylamino, carbamoyl, sulfamoyl and (C1-C4)-alkoxycarbonyl/ or a3) denotes a radical of the formula II

R1 is defined as A under ai) or a2), R2 denotes hydrogen or methyl, R3 denotes hydrogen or (C1-Cs)-alkyl/ preferably (C1-C*)-alkyl/ which is optionally monosubstituted by amino, substituted amino, hydroxyl, carboxyl, carbamoyl, guanidino, substituted guanidino, ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 5 4 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2- thienyl, 3- thienyl, 2- pyridyl, 3- pyridyl or cyclohexyl, 10 15 vhere substituted amino stands for a compound -NH-A- and substituted guanidino stands £or a compound -NH-C(NH)-NH-A, in which A is defined as under ax) or a2); B stands for a basie amino acid in the L- or D-con-figuration, which may be substituted in the side Chain; C stands for a compound of the formula Illa or Illb

G'-G'-Gly G'-NH-(CH2)n-CO (Illa) (Illb) in which

G' independently of one anotherdenotes a radical of the formula IV R4 R5 0. 20 - N - CH - C - (IV) in which 25 R4 and R3 together with the atoms carrying them form a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms, and n is 2 to 8; E stands for the radical of an aromatic amino acid; F independently of one another denotes the radical of a neutral, acidic or basie, aliphatic or aromatic amino acid which may be substituted in the side Chain, or stands for a direct bond;

(D)-Tic denotes the radical of the formula V

G is as defined above for G' or denotes a direct bond; 30 5 - 5 - LV 10720 F' is as defined for F, denotes a radical -NH-(CH2)n-, with n 2 to 8, or, if G does not denote a direct bond, can stand for a direct bond, and I is -OH, -NH2 or -NHC2H5, K denotes the radical -NH-(CH2)x-CO- with x = 1-4 or stands for a direct bond, and M is as defined for F, and their physiologically tolerable salts.

If not stated othervise, the abbreviation of an amino 10 acid radical vithout a stereodescriptor stands for the radical in the L-form (coinpare Schrdder, Lvibke; The · Peptides, Volume I, New York 1965, pages ΧΧΙΙ-ΧΧΙΙΙ; Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Volume XV/1 and 2, Stuttgart 1974), 15 such as, for example,

Aad, Abu, TAbu, ABz, 2ABz, eAca, Ach, Acp, Adpd, Ahb, Aib, 0Aib, Ala, 6Ala, AAla, Alg, Ali, Anta, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys,

Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc,

Fel, Cln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, 0Lys, ALys, Met, Mim, Min, nArg, Nle, Nva, 01y, Orn, Pan, Pec, Pen, Phe, Phg, Pie, Pro, Pro, Pse, Pya, Pyr,

Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, PThi, Thr, Thy,

Thx, Tia, Tie, Tly, Trp, Trta, Tyr, Vai.

Suitable radicals of a heterocyclic ring system of the formula IV are in particular radicals of heterocycles of the group below:

Pyrrolidine (A); piperidine (B); tetrahydroisoquinoline 20 (C); decahydroisoguinoline (D); octahydroindole (E); octahydrocyclopenta[b]pyrrole (F); 2-aza-bicyclo[2.2.2]-oetane (Ģ); 2-azabicyclo[2.2.lļheptane (H); 2-azaspiro-[4.5]decane (X); 2-azaspiro[4.4]nonane (J); spiro[(bi- 6 cyclo[2.2.l]heptane)-2,3-pyrrolidine] (Ķ); spiro[(bi- cyclo[2.2.2]octane)-2,3-pyrrolidineJ (Ļ); 2-azatricyclo-[4.3.0. le,9]decane (M); decahydrocyclohepta[b]pyrrole (Ņ); octahydroisoindole (0); octahydrbcyclopenta[c]pyrrole 5 (P); 2,3,3a,4/5,7a-hexahydroindole (Q); tetrahydrothia- zole (R); 2-azabicyclo[3.1.0]hexane (S); isoxazolidine (T); pyrazolidine (U); hydroxyproline (V); ali of which may be optionally substituted. LV 10720

θ

The heterocycles based on the abovementioned radicals are known, for example, from US-A-4/344/949, US-A-4,374, 847 , US-A-4f350r704, EP-A-50,800, EP-A-31,741, EP-A-51,020, EP-A-49,658, 5 EP-A-49,605, EP-A-29,488, EP-A-46,953, EP-A-52,870, EP-A-271,865, DE-A-3,226,768/ DE-A-3,151,690 , DE-A-3,210,496, DE-A-3,211,397, DE-A-3,211,676, DE-A-3,227,055, DE-A-3,242,151, DE-A-3,246,503 and DE-A-3,246,757. 10 Some of these heterocycles are furthermore proposed in DE-A-3,818,850.3.

If not stated othervise in the individual case, alkyl can be straight-chain or branched. The same applies to radicals derived therefrom such as alkoxy, aralkyl or 15 alkanoyl. (C6-C12)—Aryl preferably denoteš phenyl, naphthyl or biphenylyl. Radicals derived therefrom, such as aryloxy, aralkyl or aroyl, are to be formulated correspondingly.

Halo stands for fluorine, chlorine, bromine or iodine, 20 preferably for chlorine.

Possible salts are, in particular, alkali mētai or alkaline earth mētai salts, salts with physiologically tolerable amines and salts with inorganic or organic acids such as, for example, HC1, HBr, H2S0*, H3P0W maleic 25 acid, fumaric acid, citric acid, tartaric acid and acetic acid.

Preferred peptides of the formula I are those in which B denotes Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homoarginine radical, where in each case the amino 30 or guanidino group of the side chain may be sub- stituted by A as described under aj or a2); - 9 - - 9 - LV 10720 E stands for the radical of an aromatic amino acid in the L- or D-configuration, which contains 6 to 14 carbon atoms in the aryl moiety as ring members, such as phenylalanine which is optionally substi-tuted by halogen in the 2-, 3- or 4-position, tyrosine# 0-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine; F' denotes the radical of a basie amino acid in the L-or D-conf iguration, such as Arg or Lys, where the guanidino' group or amino group of the side chain may be replaced by A as deseribed under ax) or a2), or denotes a radical -NH-(CH2)n - with n * 2 to 8 and K stands for the radical -NH-(CH2)x-CO- with x = 2-4 or denotes a direct bond.

Particularly preferred peptides of the formula I are those in vhich B denotes Arg, Orn or Lys, where the guanidino group or the amino group of the side chain is unsubsti-tuted or may be substituted by (C1-C8)-alkanoyl, (C7-Ci3)-aryloyl, (C3-C9)-heteroaryloyl, (C1-C8)-alkylsul-fonyl or (C8-C12)-arylsulfonyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals may optionally be substituted, as deseribed under a2), with 1, 2, 3 or 4 identical or different radicals. E denotes phenylalanine, 2-chlorophenylalanine, 3- chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4- fluorophenylalanine, tyrosine, 0-methyltyrosine or 0-(2-thienyl)alanine; K stands for a direct bond and M stands for a direct bond 10

Very particularly preferred peptides of the formula I are those in which A denotes hydrogen, (D)— or (L)-H-Arg, (D)- or (L)-H-Lys or (D)— or (L)-H-Orn, 5 B denotes Arg, Orn or Lys, where the guanidino group or the amino group of the side chain may be sub-stituted by hydrogen, (C1-Ce)-alkanoyl, (C7-C13)-aryloyl, (C3-Cg)-heteroaryloyl, (C1-Ce)-alkylsulfonyl or (C6-Cl2)-arylsulfonyl, vhere the aryl, heteroaryl, 10 aryloyl, arylsulfonyl and heteroaryloyl radicals may optionally be substituted with 1, 2, 3 or 4 identi-cal or different radicals from the series comprising methyl/ methoxy and halogen. C denotes Pro-Pro-G^, Hyp-Pro-Gly or Pro-Hyp-Gly 15 E denotes Phe or Thia F denotes Serf Hser, Lys, Leu, Vai, Nle, Ile or Thr K stands for a direct bond H stands for a direct bond G 20 stands for the radical of a heterocyclic ring system of the formula IV, vhere the radicals of the hetero-cycles pyrrolidine (A); piperidine (B); tetrahydro-isoquinoline (C); cis- and trans-decahydroisoquino-line (D); cis-endo-octahydroindole (E), cis-exo-octahydroindole (E), trans-octahydroindole (E)r cis- 25 endo-, cis-exo-, trans-octahydrocyclopentano[b]pyr-role, (F) or hydroxyproline (V) are preferred. F’ denote Arg and I stands for 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-Thi a-Ser-(D)-Tic-Oic-Arg-OH H-{D)-Arg-Arg-Pro-Hyp-Cly- 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 invention furthermore relates to a process for the preparation of peptides of the formula I, which comprises a) reacting a fragment having a C-terminal free car-boxyl group or its activated derivative with an appropriate fragment having an N-terminal free amino group or b) synthesizing the peptide stepwise, optionally splitting off one or more protective groups temp-orarily introduced for the protection of other functions in the compound obtained according to (a) or (b) and optionally converting the compounds of the formula I thus obtained into their physiologi-cally tolerable salt.

The peptides of the present invention were prepared by generally knovm methods of peptide chemistry, see, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 15/2, preferably by means of solid phase synthesis such as described, for example, by B. Merrifield, J.Am.Chem.Soc. .85, 2149 (1963) or R. C. Sheppard, Int. J. Peptide Protein Res. 21, 118 (1983) or by equivalent knovm methods. Urethane protective groups such as, for example, the tert-butyloxy-carbonyl(Boc) or fluorenylmethoxycarbonyl(Fmoc) protective group are used as α-amino protective group. If necessary for the prevention of side reactions or for the synthesis of specific peptides, the functional groups in the side Chain of amino acids are additionally protected by suitable protective groups (see, for example, T.W. Greene, "Protective Groups in Organic Synthesis"), where 12 primarily,

Arg(Tos), Arg(Mts), Arg(Mtr), Arg(PMC), Asp(OBzl), Asp(OBut), Cys(4-MeBzl), Cys(Acm), Cys(SBut), Glu(OBzl), Glu(OBut), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-Z), Lys(Boc), Met(O), Ser(Bzl), Ser(But), Thr-(Bzl), Thr(But), Trp(Mts), Trp(CHO), Tyr(Br-Z), Tyr(Bzl) or Tyr(But) are employed.

Solid phase synthesis begins at the C-terminal end of the peptide with the coupling of a protected amino acid to an appropriate resin. Starting materiāls of this type may be obtained by linking a protected amino acid via an ester or amide bond to a polystyrene or polyacrylamide resin modified with a chloromethyl, hydroxymethyl/ benzhydryl-amino(BHA) or methylbenzhydrylamino(MBHA) group. The resins used as support materiāls are commercially obtain-able. BHA and MBHA resins are usually used if the peptide synthesized is intended to have a free amide group at the C-terminus. If the peptide is intended to have a second-ary amide group at the C-terminal end, a chloromethyl or hydroxymethyl resin is used and the splitting off is carried out using the corresponding amines. If it is vished to obtain, for example, the ethylamide, the peptide can be split off from the resin using ethylamine, the splitting off of the side chain protective groups subsequently being carried out by means of other suitable reaģents. If it is intended to retain the tert-butyl protective groups of the amino acid side chain in the peptide, the synthesis is carried out using the Fmoc protective group for temporary blocking of the e-amino group of the amino acid using the raethod described, for example, in R.C. Sheppard, J.Chera.Soc., Chem.Comm 1982. 587, the guanidino function of the arginine being protected by protonation with pyridinium perchlorate and the protection of the other functionalized amino acids in the side chain being carried out using benzyl protective groups which can be split off by means of catalytic transfer hydrogenation (A. Felix et al. J. Org. Chem. 13. 4194 (1978) or by means of sodium in liguid ammonia - 13 - LV 10720 (W. Roberts, J.Am.Chem.Soc. 1_S, 6203 (1954)).

After splitting off the amino protective group of the amino acid coupled to the resin using a suitable reaģent, such as, for eXample, trifluoroacetic acid in methylene 5 chloride in the case of the Boc protective group or a 20% strength solution of piperidine in dimethylformamide in the case of the Fmoc protective group, the subsequently protected amino acids are successively coupled in the desired sequence. The intermediately resulting N-terminal 10 protected peptide resins are deblocked by means of the reaģents described above before linkage with the subse-guent amino acid derivative.

Ali possible activating reaģents used in peptide syn-thesis can be used as coupling reaģents, see, for ex-15 ample, Houben-Weyl, Methoden der organischen Cheraie (Methods of Organic Chemistry), Volume 15/2, in par-ticular, hovever, carbodiimides such as, for example, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropy1-carbodi-imide or N-ethyl-N' - (3-dimethylaminopropyl) -carbodiimide. 20 The coupling can in this case be carried out directly by addition of amino acid derivative and the activating reaģent and, if desired, a racemization-suppressing additive such as, for example, l-hydroxy-benzotriazole (HOBt) (W. Konig, R. Geiger, Chem. Ber. 103, 708 (1970)) 25 or 3-hydroxy-4-oxo-3,4-dihydrobenzo-triazine (HOObt) (W. Konig, R. Geiger, Chem.Ber. 103. 2054 (1970)) to the resin or, hovever, the preactivation of the amino acid derivative as symmetrical anhydride or HOBt or HOObt ester can be carried out separately and the solution of 30 the activated species in a suitable solvent can be added to the peptide resin capable of coupling.

The coupling or activation of the amino acid derivative vith one of the abovementioned activating reaģents can be carried out in dimethylformamide, N-methylpyrrolidone or methylene chloride or a mixture of the solvents men-tioned. The activated amino acid derivative is 35 14 customarily employed in a 1.5 to 4 fold excess. In cases in which an incomplete coupling takes place, the coupling reaction is repeated without previously carrying out the deblocking of the α-amino group of the peptide resin necessary for the coupling of the following amino acid.

The successful course of the coupling reaction can be monitored by means of the ninhydrin reaction/ such as described, for example, by E. Kaiser et al. Anal. Biochem. 34. 595 (1970). The synthesis can also be auto-mated/ for example using a peptide synthesizer modei 430A from Applied BiosystemS/ it being possible either to use the synthesis program provided by the apparatus manufac-turer or else, hovever, one set up by the user himself. The latter are in particular employed in the use of amino acid derivatives protected with the Fmoc group.

After synthesis of the peptides in the previously described manner/ the peptide can be split off from the resin using reaģents, such as, for example, liguid hydrogen fluoride (preferably in the peptides prepared according to the Boc method) or trifluoroacetic acid (preferably in the peptides synthesized according to the Fmoc method). These reaģents not only cleave the peptide from the resin but also the other side chain protective groups of the amino acid derivative. In this manner, the peptide is obtained in the form of the free acid in addition using BHA and MBHA resins. With the BHA or MBHA resins, the peptide is obtained as acid amide when splitting off is carried out using hydrogen fluoride or trifluoromethanesulfonic acid. Additional processes for the preparation of peptide amides are described in German Patent Applications P 37 11 866.8 and P 37 43 620.1. The splitting off of the peptide amides from the resin here is carried out by treatment with medium strength acids (for example trifluoroacetic acid) usually used in peptide synthesis, cation entrainer substances such as phenol, cresol, thiocresol, anisole, thioanisole, ethane-dithiol, dimethyl sulfide, ethyl methyl sulfide or - 15 - LV 10720 similar cation entrainers customary in solid phase synthesis being added individually or as a mixture of two or more of these auxiliaries. In this case, the tri-fluoroacetic acid can also be used diluted by suitable 5 solvents, such as, for example, methylene chloride.

If the tert-butyl or benzyl side Chain protective groups of the peptides are to be retained, the splitting off of the peptide synthesized on a particularly modified support resin is carried out using 1% trifluoroacetic 10 acid in methylene chloride, such as described, for example, in R.C. Sheppard J.Chem. Soc., Chem. Comm. 1982. 587. If individual tert-butyl or benzyl side chain protective groups are to be retained, a suitable combination of synthesis and splitting off methods is 15 used.

For the synthesis of peptides having a C-terminal amide grouping or an ω-amino or <d-guanidinoalkyl grouping, the modified support resin described by Sheppard is likevise used. After the synthesis, the peptide fully protected in 20 the side chain is split off from the resin and subse-quently reacted with the appropriate amine or ω-amino-alkylamine or w-guanidinoalkylaraine in classical solution synthesis, it being possible for optionally present additional functional groups to be temporarily protected 25 in a knovm manner.

An additional process for the preparation of peptides having an w-aminoalkyl grouping is described in German Patent Application P 36 35 670.0.

The peptides of the present invention were preferably 30 synthesized by two general protective group tactics using the solid phase technigue:

The synthesis vras carried out using an automatic peptide synthesizer modei 430 A from Applied Biosystems, with Boc or Fmoc protective groups for temporary blockage of i.ne 16 α-amino group.

When using the Boc protective group, the synthesis cycles pre-programmed by the manufacturer of the apparatus vere used for the synthesis.

The synthesis of the peptides having a free carboxyl group on the C-terminal end was carried out on a 4-(hydroxymethyl)phenylacetamidomethylpolystyrene resin functionalized with the corresponding Boc amino acid (R.B. Merrifield, J. Org. Chem. 4.3, 2845 (1978)) frora Applied Biosystems. An MBHA resin from the same firm was used for the preparation of the peptide amides. N, N'-Dicyclohexylcarbodiimide or N,N'-diisopropylcarbodi-imide were used as activating reaģents. Activation- was carried out as the symmetricai anhydride, as the HOBt ester or HOObt ester in CH2C12/ CH2C12 - DMF mixtures or NMP. 2-4 equivalents of activated amino acid derivative were employed for the coupling. In cases in which the coupling took place incompletely, the reaction was repeated.

During the use of the Fmoc protective group for the temporary protection of the α-amino group, our own synthesis programs vere used for synthesis using the automatic peptide synthesizer modei 430A from Applied Biosystems. The synthesis was carried out on a p-ben-zyloxybenzyl alcohol resin (S. Wang, J.Am.Chem.Soc. 95. 1328 (1973)) from Bachem vhich vas esterified by a knovn method (E. Atherton et al. J.C.S. Chem. Comm. 1981. 336) using the appropriate amino acid. The activation of the amino acid derivatives as KOBt or HOObt esters vas carried out directly in the amino acid cartridges pro-vided by the apparatus manufacturer by addition of a solution of diisopropylcarbodiimide in DMF to the pre-viously veighed-in mixture of amino acid derivative and HOBt or HOObt. Fmoc-amino acid-OObt esters prepared in substance can Irkevise be employed as described in European Patent Application 87,107,634.5. The splitting - 17 - LV 10720 off of the Fmoc protective group was carried out using a 20% strength solution o£ piperidine in DMF in the reaction vessel. The excess of reactive amino acid derivative used was 1.5 to 2.5 equivalents. If the 5 coupling was not complete, it was repeated as in the Boc method.

The peptides according to the invention have, individu-ally or in combination, a bradykinin antagonist action which can be tested in various models (see Handbook of 10 Exp. Pharmacol. Vol. 25, Springer Verlag, 1970, p. 53- 55), for example on the isolated rat uterus, on the guinea pig ileuīn or on the isolated pulmonary artery of the guinea pig.

For testing the peptides according to the invention on 15 the isolated arteria pulmonalis, guinea pigs (Dunkin

Hartley) having a weight of 400 - 450 g are sacrificed by a blow to the back of the neck.

The thorax is opened and the arteria pulmonalis is carefully dissected out. The surrounding tissue is 20 carefully removed and the arteria pulmonalis is cut spirally at an angle of 45°.

The vessel strip of 2.5 cm length and 3-4 mm width is fixed in a 10 ml capacity organ bath vhich is filled with Ringer solution. 25 Composition of the solution in mmol/1

NaCl 154 KC1 5.6 CaCl2 1.9 NaHCOj 2.4 Glucose o in 95% 02 and 5% C02 is bubbled through the solution, which is varmed to 37eC. The pH is 7.4 and the preload on the vessel strip is 1.0 g. 18

The isotonic contraction changes are detected using a Iever arrangement and an HF modēm (position sensor) from Hugo Sachs and recorded on a compensating recorder (BEC, Goerz Metrawatt SE 460). 5 After equilibration for 1 hour, the experiment is begun. After the vessel strips have achieved their maximum sensitivity to 2 χ 10'7 mol/1 of bradykinin - bradykinin leads to a contraction of the vessel strips - the pep-tides are alloved to act for 10 minūtes in each case in 10 the doses 5 x 10‘® - 1 χ 10"3 mol/1 and/ after adding bradykinin again, the decrease in the effect of bradykin-in as opposed to the control is compared.

For the detection of a partial agonistic effect, the peptides are used in the doses 1 χ 10*5 - 1 χ 10'3 mol/1. 15 The IC50 values of the peptides according to the invention calculated from the dose-effect curves are shovn in Table 1.

Table 1;

Compound IC30 [M] 20 - H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-$er-(D)-Tic-Phe-Arg-OH 4,6 * 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(0)-Tic-Thia-Arg-OH 2,1 · 10' H-(D)-Arg-Arg-Pro-Hyp-G1y-Phe-Ser-(D)-Tic-Phe-Arg-0H 1,2 · 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Glo-(D)-Tic-Phe-Arg-OH 2,4 · 10' 25 H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-T1c-Phe-Arg(Mtr)-0H 2,5 · 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-5er*(D)-Tic-Pro-Arg-0H 2,5 · 10' H-(D)-Arg-Ārg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH 1,9 · 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 5,6 · 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-TMa-Ser-(5-Ala-(D)-T1c-Aoc-Arg-0H 1,7 · 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly-(D)-Tic-Aoc-Arg-OH 3,9 · 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-(D)-Tic-(D,L)-Oic-Arg-OH 3,2 · 10' H-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 4,8 · 10' H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Tic-Arg-OH 1,7 · 10' 30 - 19 - LV 10720

Compound IC50 [M] H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 1,1 · 10"8 H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH 4,6 · 10”® H-(D)-Tyr-Arg-Pro-Hyp-G1y-Thia-Ser-(D)-Tic-Aoc-Arg-0H 6,2 · 10'® H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-5er-(D)-Tic-(D)-Dic-Arg-0H 2,6 · 10'5 H-(D)-Arg-Arg*Pro-Hyp-G1y-Thia-Ser-(D)-Tic-0ic-Arg-0H 5,4 · 10'® H-(D)-Arg-Lys-Pro-Hyp-Gly-Phe-$er-(D)-Tic-Aoc-Arg-OH 3,2 · 10'7 H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-T1c-0ic-Arg-0H 6,8 10'9 H-(D)-Arg-Arg-(N02)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-0H 6,4 · 10'8 H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH 4,2 · 10'9 H-(D)-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH 3,4 · 10'7 H-Arg-(Tos)-Pro-Hyp-Gly-Phe-$er-(D)-Tic-Dic-Arg-OH 3,0 · 10'8 H-Arg-(Tos)-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Dic-Arg-OH 1,8 · 10*8

The therapeutic utility of the peptides according to the invention includes ali pathological States which are mediated, caused or supported by bradykinin and brady-kinin-related peptides. This includes, inter alia, traumas, such as wounds, bums, rashes, erythemas, edemas, angina, arthritis, asthma, allergies, rhinitis, shock, inflammations, low blood pressure, pain, itching and changed sperm motility.

The invention therefore also relates to the use of peptides of the formula I as medicaments, and to phanna-ceutical preparations which contain these compounds.

Pharmaceutical preparations contain an effective amount of the active substance of the formula I - individually or in combination - together with an inorganic or organic pharmaceutically utilizable excipient. Ādministration can be carried out enterally, parenterally - such as, for example, subcutaneously, i.m. or i.v. sublingually, epicutaneously, nasally, rectally, intra-vaginally, intrabuccally or by inhalation. The dosage of the active substance depends on the mammai species, the body weight, age and on the manner of administration. 20

The pharmaceutical preparations of the present invention are prepared in solution, mixing, granulating or tablet coating processes known per se.

For oral administration or application to the mucosa, the active compounds are mixed with the customary additives for this, such as exci.pi.ents, stabilizers or inert diluents, and brought into suitable forms for administration, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or agueous, alcoholic or oily Solutions, by customary methods. Inert excipients which may be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular maize starch. In this case, the preparation may be present both as dry and raoist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflover oil and cod liver oil. A preparation for topical application may be present as an agueous or oily solution, lotion, emulsion or gel, ointment or fatty ointment or, if possible, in spray form, it being possible to improve the adhesion, if desired, by addition of a polymer.

For the intranasal form of administration, the compounds are mixed with the customary auxiliaries for this, such as stabilizers or inert diluents, and brought into suitable forms for administration, such as agueous, alcoholic or oily suspensions or agueous, alcoholic or oily Solutions, by customary methods. Chelating aģents, ethylenediamine-N,N,N',Ν'-tetraacetic acid, citric acid, tartaric acid or their salts may be added to agueous intranasal preparations. Administration of the nasal Solutions can be carried out by means of metered atom-izers or as nasal drops, having a viscosity-increasing component, or nasal gels or nasal creams. - 21 LV 10720

For administration by inhalation, atomizers or pressurized gas packs using inert carrier gases can be used.

For intravenouS, subcutaneous, epicutaneous or intra-5 dermal administration, the active compounds or their physiologically tolerable salts, if desired with the pharmaceutically customary auxiliaries, for example for isotonisizing or adjusting pH, and solubilizers, emul-sifiers or other auxiliaries, are brought into solution, 10 suspension or emulsion.

Because of the short half-lives of some of the medica-ments described in body fluids, the use of injectable sustained release preparations is efficient. Medicament forms which raay be used are, for example, oily crystal 15 suspensions, microcapsules, rods or implants, it being possible to synthesize the latter from tissue-corapatible polyrners, in particular biodegradable polymers, such as, for example, those based on polylactic acid/ polyglycolic acid copolymers or human albumin. 20 A suitable dose range for forms for topical application and administration by inhalation are Solutions containing 0.01-5 mg/ml, and with forms for systemic administration 0.01-10 mg/kg is suitable.

List of abbreviations: 25 The abbreviations used for amino acids correspond to the three-letter code customary in peptide chemistry as described in Europ. J. Biochem. 138. 9 (1984). Addition-ally used abbreviations are listed below.

Acm Acetamidomethyl «-Ahx € -Aminohexanoyl

Aoc cis, endo-2-Azabicyclo [3.3.0 ]octane-3-S- carbonyl

Boc tert-Butyloxycarbonyl

But tert-Butyl 30 22 22 Bzl Benzyl Cl-Z 4-Chlorobenzyloxycarbonyl DMF Dimethylformamide Dnp 2,4-Dinitrophenyl Fmoc 9-Fluorenylmethoxycarbonyl Me Methyl 4-Mebzl 4-Methylbenzyl Mtr 4-Methoxy-2,3,6-trimethylphenylsulfonyl Mts Mesitylene-2-sulfonyl NMP N-Methylpyrrolidine Oic cis-endo-octahydroindol-2-ylcarbonyl Opr Isoxazolidin-3-ylcarbonyl Pmc 2,2,5,1,8-Pentamethylchroman-6-sulfonyl TFA Trifluoroacetic acid Tcs 4-Methylphenylsulfonyl Thia 2-Thienylalanyl Tic 1/2,3,4-Tetrahydroisoquinolin-3-ylcarbonyl Trt Trityl 10 15

The following examples are intended to illustrate the 20 preferred methods for solid phase synthesis of the peptides according to the invention, vithout limiting the invention thereto.

The amino acid derlvatives below were used: 25

Fmoc-Arg(Mtr)-OH, Boc-(D)-Arg-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Hyp-OH, Fmoc-Pro-OObt, Fmoc-Gly-OObt, Fmoc-Phe-OObt, Fmoc-Ser(tBu)-OObt, Fmoc-(D)-Tic-OH, Fmoc-Gln-OH, Fmoc-Aoc-OH, Fmoc-Thia-OH, Fmoc-Opr-OH, Fmoc-{D}-Asn-OH, Fmoc-fi-Ala-OH, Fmoc-Oic-OH.

Example 1:

30 H-(D) -Axg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH was synthesited stepwise using a peptide synthesizer modei 430 A from Applied Biosystems by the Fmoc method on a p-benzyloxybenzyl alcohol resin from Novabiochem (loading about 0.5 minol/g of resin) esterified with Fmoc-Arg(Mtr)-OH. 1 g of the resin was employed and the 35 - 23 - LV 10720 synthesis was carried out with the aid of a synthesis program modified for the Fmoc raethod.

In each case 1 nunol of the amino acid derivative having a free carboxyl group together with 0.95 mmol of HOObt 5 was weighed into the cartridges of the synthesizer. The preactivation of these amino acids was carried out directly in the cartridges by dissolving in 4 ml of DMF and adding 2 ml of a 0.55 mol solution of diisopropyl-carbodiimide in DMF. 10 The HOObt esters of the other amino acids were dissolved in 6 ml of NMP and then similarly coupled to the resin previously deblocked using 20% piperidine in DMF, like the amino acids preactivated in situ. After completion of the synthesis, the peptide was split off from the resin 15 using thioanisole and ethanedithiol as cation entrainers, with simultaneous removal of the side Chain protective groups using trifluoroacetic acid. The residue obtained after stripping off the trifluoroacetic acid was repeat-edly digested with ethyl acetate and centrifuged. The 20 residue vhich remained was chromatographed on ®Sephadex LH 20 using 10% strength acetic acid. The fractions containing the pure peptide were combined and freeze-dried. MS(FAB) Ϊ 1294 (M+H) 25 The peptides of Examples 2 to 24 below were prepared and purified analogously to Example 1.

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-Arg-OH MS(FAB) : 1306 (M+H) 24

Ezample 4: Η-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-S er-(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)

Ezample 7: H-{D)-Arg-Arg-Hyp-Pro-Gly-Phe-Trp-{D)-Tic-Phe-Arg- OH MS(FAB) : 1393 (M+H) 5 Ezample 8: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH MS(FAB) : 1250 (M+H)

Ezample 9: H- (D)-Arg-Arg-Hyp-Pro-Cly-Thia- (D)-Asn- (D)-Tic-Thia-Arg-OH MS(FAB) : 1333 (M+H)

Ezample 10: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Opr-(D)-Tic-Thia-Arg-OH MS(FAB) : 1301 (M+H)

Ezample 11: H- (D) - Arg- Arg- Hyp-Pro-Gly- Thia- (D)-Gln- (D)-Tic-Thia- Arg-OH MS(FAB) : 1347 (M+H)

Ezample 12: H-(D)-Arg-Arg-Hyp-Pro-G1y-Thia-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H) 0 Example 13: H-(D)-Arg-Arg-Hyp-Pro-Cly-Thia-Ser-(D)-Tic-Pro-Phe-OH MS(FAB) : 1241 (M+H) - 25 - LV 10720

Ezample 14: H- (D) - Arg- Arg- Hyp-Pro- Gly- Thia- Ser- (D) - Tic- Pro- Phe- Arg- OH MS(FAB) : 1397 (M+H)

Ezample 15: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-B-Ala- (D)-Tic-Pro-Arg-OH MS(FAB) : 1321 (M+H)

Ezample 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-Arg-OH MS(FAB) : 1330 (M+H) 5 Ezample 18: H- (D)-Arg-Arg-Pro-Aoc-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OH MS(FAB) : 1330 (M+H)

Ezample 19: H- (D) - Arg- Arg-Hyp- Pro-Gly-Thia- Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1290 (M+H)

Ezample 20: H-(D)-Arg-Arg-Opr-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH MS(FAB) : 1236 (M+H)

Ezample 21: H- {D) - Arg- Arg- Pro- Opr- Gly- Thia- Ser- (D)-Tic-Pro- Arg-OH MS(FAB) : 1236 (M+H)

Ezample 22: H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Opr-Arg-OH MS(FAB) : 1252 (M+H)

Ezample 23: H-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1290 (M+H) 10 26

Ezample 24: H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1290 (M+H)

Ezamples 25 - 27:

H- (D) -Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH 5 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-10 Arg(Mtr)-OH are prepared analogously to Example 1, the splitting off of the side chain protective groups and the peptide from the resin by means of trifluoroacetic acid being limited to 30 minūtes at room temperature. Under the conditions 15 thus selected, only a negligible splitting off of the Mtr protective group on the arginine takes place. The par-tially deblocked peptides are separated by chromatography on reverse phase material and purified. 25: 20

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-Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-OH MS(FAB): 1718 (M+H) 27: 25

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

The peptides of Examples 28-31 below were prepared and purified analogously to Examples 25 - 27.

Example 28: H-(D)-Arg-Arg(Mtr)-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Pro-Arg-OH MS(FAB) : 1462 (M+H) - 27 - LV 10720

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: 5 H-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH2) <-ΝΗ2.

The peptide synthesis was carried out on 1 g of an amino-methyl resin which was modified with an attachment group of the type /c=\

Fmoc-NH- (CH2)4-NH-CO-0-CH,-C C-O-CH,-v. y ^ co- c-c 10 15 20 described in EP-A 264,802, using Fraoc-amino acid-OObt esters with an automatic peptide synthesizer (modei 430A from Applied Biosystems) and sļ^nthesis pro grams which have themselves been modified. To this end, in each case 1 mmol of the appropriate amino acid derivative was veighed into the cartridges provided by the manufacturer, and Fmoc-Arg(Mtr)-OH, Fmoc-Hyp-OH and Fmoc-(D)-Tic-OH were veighed into the cartridges together vith 0.95 mmol of HOObt. The preactivation of these amino acids in situ was carried out directly in the cartridges 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 vere dissolved in 6 ml of NMP and then coupled to the resin previously deblocked using 20% piperidine in DMF, like the amino acids preactivated in situ, the amino acids activated in situ being doubly coupled. After completion of synthesis, the peptide 4- 25 28 aminobutylamide was split off from the resin with simul-taneous removal of the side chain protective groups with trifluoroacetic acid which contained thioanisole and m-cresol as cation entrainers. The residue obtained after stripping off the trifluoroacetic acid was repeatedly digested with ethyl acetate and centrifuged. The crude peptide which remained was chromatographed on ®Sephadex G25 using 1N acetic acid. The fractions containing the pure peptide were combined and freeze-dried.

The compounds of Examples 33-35 were prepared analo-gously to Example 32s

Ezample 33: H-D-Arg-Arg-Hyp-Fro-Gly-Phe-Ser- (D)-Tic-Phe-NH- (CH2)4"*^2

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

Ezample 35: HOOC- (CH2)2-CO- (D)-Arg-Hyp-Pro-Gly-Phe-Ser- (D)-Tic-Phe-NH- (ch2)4-nh2

The exainples 36 to 161 were synthesized according to the method described under Example 1.

Ezample 36: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thi a-Ser-Gly-(D)-Tic-Pro-Arg-OH MS(FAB) : 1307 (M+H)

Exan*ple 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) - 29 - LV 10720

Example 39: H- (D)-Arg-Arg-Hyp-Pro-Cly-Thia-Ser-β-AIa- (D) - Tic-Aoc-Arg-OH MS(FAB) : 1361 (M+H)

Example 40: H- (D) - Arg- Arg- Pr o- Hyp- Gly- Thi a- Ser- β- AI a- (D)-Tic-Aoc- Arg-OH MS(FAB) : 1361 (M+H)

Example 41: H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tlc-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) 5 Example 43: H- (D) - Arg- Arg- Pro- Hyp- Gly- Thia- Cly- (D)-Tic-Aoc- Arg-OH MS(FAB) : 1260 (M+H)

Example 44: H- (D) - Arg-Arg-Hyp-Pro-Gly-Thia-Cly- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1260 (M+H)

Exa2sple 45: H-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1290 (M+H)

Example 46: 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) 1 Example 48: H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Tic-Arg-OH MS(FAB) : 1312 (M+H) 30

Ezample 4 9: H- (D)-Arg-Arg-Pro-Pro-Cly-Thia-Ser- (D)-Tic-Aoc-Arg-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)

Ezample 51: H- (D) - Arg- Arg- Hyp- Pro- G1 y- Aoc- Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H)

Ezample 52: H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-0-Ala- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1274 (M+H) 5 Ezample 53: H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia- 0-Ala- (D) - Tic- Aoc- Arg-OH MS(FAB) : 1274 (M+H)

Ezample 54: H- (D) - Arg- Arg- Hyp- Pro- Gly- Asp- Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H)

Ezample 55: H- (D)-Arg-Arg-Pro-Hyp-Gly-Asp-Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1252 (M+H)

Ezample 56: H- (D) - Arg- Arg- Hyp- Pro- Cly- Trp- Ser- (P)-Tic-Aoc-Arg-OH MS(FAB) : 1323,7 (M+H)

Ezample 57: H- (D)-Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH MS(FAB) : 1297,7 (M+H) 10 Ezample 58: H- (D) - Arg- Arg-Pro-Hyp- Gly-Thia- Ser- (D)-Tic- (D)-Oic-Arg-OH MS(FAB) : 1304,6 (M+H) - 31 - LV 10720

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-Cly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1289 (M+H)

Example 61: H-(D)-Arg-Lys-Pro-Hyp-Cly-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) 5 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-Olc-Arg-OH MS(FAB) : 1298 (M+H)

Exanple 65: H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1298 (M+H)

Exanple 66: H- (D)-Arg-Arg-Pro-Pro-Cly-Phe-Ser- (D)-Tic-Oic-Arg-OH MS(FAB) : 1282 (M+H)

Example 67: H-(D)-Arg-Arg(N02)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH MS(FAB) : 1329,7 (M+H)

Example 68: H-(D)-Arg-Arg(N02) - Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB): 1343 (M+H) 32

Example 69: H-(D)-Arg-Arg(N02)*Pro-Pro-Cly-Phe-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1327 (M+H)

Example 70:

Η*(D)-Arg-Arg(N02)-Pro-Pro-Cly-Thi*-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1333 (M+H)

Example 71:

H-(D)-Arg-Arg(N02)-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1349 (M+H)

Ezample 72:

H-Arg(Tos)-Pro-Hyp-Gly-Thla-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1302 (M+H) 5 Example 7 3: H-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1142 (M+H)

Ezample 74: H-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1233 (M+H)

Ezample 75: H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1296 (M+H)

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

Example 77: H-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1282 (M+H) - 33 - - 33 - LV 10720

Ezample 78:

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

Ezample 79:

H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1438 (M+H)

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

Ezample 81: H-Arg-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1142 (M+H) 5 Ezample 82: H- Ly s (- CO- NH- CgHs) - Hyp- Pro- Gly- Phe- Ser- D-Tic-Oic- Arg- OH MS(FAB) : 1233 (M+H)

Ezample 83: H- Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1296 (M+H)

Ezample 84: H-Lys (Nicotinoyl)-Hyp-Pro-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1219 (M+H)

Ezample 85: H-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1282 (M+H)

Ezample 86:

Ac-Arg(Tos)-Hyp-Pro-Cly-Phe-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1324 (M+H) 10 Ezample 87: H- D- Arg- Arg (Tos) - Hyp- Pro- Gly- Phe- Ser- D- Tic- Aoc- Arg- OH MS(FAB) : 1438 (M+H) 34

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

Example 89: 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)

Example 91: H-Arg(Tos)-Pro-Pro-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1280 (M+H) 5 Example 92: H-Lys(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-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)

Exanple 96: H-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg- OH MS(FAB) : 1148 (M+H) 10 Example 97: H- Lys (- CO- NH- C&H5) - Pro- Hyp- Gly- Thia- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1239 (M+H) - 35 - LV 10720

Ezample 98: H-Lys(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H)

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

Ezample 100:

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

Ezample 101: H- D- Arg- Arg (Tos) - Pro-Hyp- Gly- Thia- Ser-D- Tic- Aoc- Arg- OH MS(FAB) : 1444 (M+H) 5 Ezample 102: H-Arg-Hyp-Pro-G1y-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1148 (M+H)

Ezample 103: H-Lys(-CO-NH-CgH5)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1239 (M+H)

Ezample 104: * H-Lys(Nicotinoyl)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H)

Ezample 105: H-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1288 (M+H)

Ezample 106:

Ac-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1330 (M+H) 10 Ezample 107:

H-D-Arg-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1440 IM+H) 36

Ezample 108: H-Lys(-CO-NH-CgH5)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1225 (M+H)

Ezample 109:

H-Lys(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1209 (M+H)

Ezample 110: H-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB): 1272 (M+H)

Ezample 111:

Ac-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH MS(FAB) : 1314 (M+H) 5 Ezample 112: H-D-Arg-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH 'MS(FAB) : 142B (M+H)

Ezample 113:

H-D-Arg-Lys(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1365 (M+H)

Ezample 114:

H-D-Arg-Lys(-CO-NH-C&H5)-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)

Ezample 116:

H- Lys-Lys-(Nicot inoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1337 (M+H) -37- LV 10720

Ezample 117:

H- Ly s- Lys (- CO- NH- C6H5) - Pro- Pr o- 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)

Ezample 119:

H- D- Arg- Lys (Nicot inoyl) - Pro- Hyp- Gly- Thia- Ser- D- Tic- Oic- Arg-OH MS(FAB) : 1381 (M+H)

Ezample 120:

H- D- Arg- Lys- (CO-NH- CgH^) - Pro- Hyp- Gly- Thi a- Ser- D- Tic- Oic-Arg-OH MS(FAB) : 1395 (M+H)

Ezample 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 (- CO- NH- C6HS) - Pro- Hyp-Gly- Thia- Ser- D- Tic- Oic-Arg-OH MS(FAB) : 1367 (M+H)

Ezample 123:

H- Lys- Lys (Nicotinoyl) - Pro-Hyp- Cly-Thia- Ser-D- Tic- Oic-Arg-OH MS(FAB) : 1353 (M+H)

Ezample 124: H- Lys-Arg{ Tos)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg- OH MS(FAB) : 1430 (M+H) 38

Ezample 125:

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+H)

Ezample 128: H- Lys- Lys (Nicot inoyl) - Pro- Pro- Gly- Phe- Ser-D- Tic- Oic-Arg- OH MS(FAB) : 1331 (M+H) 5 Ezample 129: H- Lys- Ly s (- CO- NH- C6H5) - Pro- Pro- Gly- Phe- Ser-D- Tic- Oic- Arg- OH MS(FAB) : 1345 (M+H)

Ezample 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 (Nicot inoy 1) - Pro-Hyp- Gly- Phe- Ser-D- Tic- Oic- Arg-OH MS(FAB) : 1375 (M+H)

Ezample 132:

H-D-Arg-Lys(-CO-NH-C6H5)-Pro-Hyp-Gly- Phe-Ser-D-Tic-Oic- Arg-OH MS(FAB) : 1389 (M+H)

Ezample 133: H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1452 (M+H) -39- LV 10720

Ezample 134: H-Lys-Lys(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1347 (M+H)

Ezample 135:

H-Lys-Lys(-CO-NH-CgH^)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic- Arg-OH MS(FAB) : 1361 (M+H)

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

Ezample 137:

H-D-Arg-Orn(Nicot inoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oi c-Arg-OH MS(FAB) : 1351 (M+H) 5 Ezample 138:

H- D-Arg-Orn(-CO-NH-C6H5)-Pro-Pro-Gly-Thi a-Ser-D-Tic-Oic-Arg-OH MS(FAB) s 1428 (M+H)

Ezample 139:

H-Lys-Orn(Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1323 (M+H)

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

Ezample 141:

H-D-Arg-Orn(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1367 (M+H) 40

Ezample 142: H-D-Arg-Orn(-CO-NH-C6H5)-Pro-Hyp-Cly-Thia-Ser-D-Tic-Oic-

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

Ezample 143: H-Lys-Orn(Nicotinoyl)-Pro-Hyp-Cly-Thia-Ser-D-Tic-Oic- Arg- OH MS{FAB) : 1339 (M+H)

Example 144:

H-Lys-Orn(-CO-NH-)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic- Arg-OH MS(FAB) : 1353 (M+H)

Ezample 145:

H-D-Arg-Orn(Nicot inoy1)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic- Arg-OH MS(FAB) : 1345 (M+H) 5 Ezample 146: H-D-Arg-Orn(-CO-NH-C6H5)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-

OH MS(FAB) : 1359 (M+H)

Ezample 147: H-Lys-Orn{Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1317 (M+H)

Ezample 148:

H- Lys-Orn (- CO- NH- C6HS) - Pro- Pro- Gly-Phe- Ser-D- Tic- Oic- Arg-OH MS(FAB) : 1331 (M+H)

Ezample 149:

H-D-Arg-Orn(Nicotinoyl)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH MS(FAB) : 1361 (M+H) - 41 - LV 10720

Example 150:

H-D-Arg-Orn(CO-NH-C6H5)-Pro-Hyp-Cly-Phe-Ser-D-Tic-Oic-Arg-OH MS(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- C&H5) -Pro-Hyp-Cly- 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- Ly s - 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-Cly-Thia-Ser-(D)-Tic-Oic-Arg-OH MS(FAB) : 1232 (M+H) 42

Example 159: H- Lys-Lys-Pro- Hyp- Gly- Thia- Ser- (D) - Tic- Oic- Arg- OH MS(FAB) : 124Θ (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) : 1242 (M+H)

The Examples 162-164 were prepared analogously to Example 5 32 using the resin having the structure F mec-NH OCH3

CH2 C-0

NH

ch2 I (polystyrene) described in EP-A 322/348.

Example 162: H- D- Arg- Arg- Pro- Hyp- Gly- Phe- Ser- D- Tic- Aoc- Arg- NH2 MS(FAB) : 1283 (M+H)

Example 163: H- D- Arg- ARg- Hyp- Pro- Gly- Phe- Ser- D- Tic- Aoc- Arg- NH2 MS(FAB): 1283 (M+H) LV 10720 - 43 -

Example 164: H-D-Arg-Arg-Pro-Pro-Cly-Phe-Ser-D-Tic-Aoc-Arg-NH2 MS(FAB): 1267 (M+H) -1- LV 10720

Patent claims:

1. A peptide of tha formula I A-B-C-E-F-K-(D)-Tic-G-M-F'-I (I) in which A ax) danotas hydrogen, (Cx-C8) -alkyl, (Ci-C8) -alkanoyl, (Ci-C8) -alkoxycarbonyl or (Ci-C8) -alkylsulfonyl, in which in each casa 1,2 or 3 hydrogan atoms ara optionally replaced by 1, 2 or 3 identical or different radicals from the saries comprising carboxyl, amino, (Ci-C4) -alkyl, (Ci-Ci) -alkylamino, hydroxyl, (C1-C4) -alkoxy, halogen, di- (Cx-C«) -alkylamino, carbamoyl, sulfamoyl, (C1-C4) -alkoxycarbonyl, (Ce-Ci2) -aryl and (Ce-Cia)-aryl-(Ci-Cs)-alkyl, or in which in aach casa 1 hydrogen atan is optionally replaced by a radical frcm the saries comprising (C3-C8) -cycloalkyl, (C1-C4) -alkylsulfonyl, (C1-C4) -alkylsulfinyl, (Ce-Cia) -aryl- (C1-C4) -alkylsulfonyl, {Ce-Ci2) -aryl- (C1-C4) -alkylsulfinyl, (C6-C12) -aryloxy, (C3-C9) -hataroaryl and (C3-C9) -hataroaryloxy -2- and 1 or 2 hydrogen atoms ara replacad by 1 or 2 identical or different radicals from tha saries comprising carboxyl, amino, (Ci-C4)-alkylamino, hydroxyl, (C1-C4) -alkoxy, halogen, di- (C1-C4) -alkylamino, carbamoyl, sulfamoyl, (C1-C4) -alkoxycarbonyl, (C6-C12) -aryl and (Ce-Cu) -aryl- (Ci-Cs) -alkyl, a2) denotes (C3-C8)-cycloalkyl, carbamoyl, which may be optionally substituted on the nitrogen by (Ci-C6) -alkyl or (Ce-Ci2) -aryl, (C6-Ci2) -aryl, (C7-Cia) -aryloyl, (C6-Ci2) -arylsulfonyl or (C3-C9) -hetaroaryl or (C3-C9)-heteroaryloyl, whara in tha radicals dafined under ax) and a2) in each casa hetaroaryl, aryloyl, arylsulfonyl and heteroaryloyl is optionally substituted by 1, 2, 3 or 4 identical or different radicals from the series comprising carboxyl, amino, nitro, (C1-C4) -alkylamino, hydroxyl, (C1-C4) -alkyl, (C1-C4) -alkoxy, halogen, cyano, di- (C1-C4) -alkylamino, carbamoyl, sulfamoyl and (C1-C4)-alkoxycarbonyl, or -3- LV 10720 a3) denotes a radical of the formula II R1 - N -CH - C - r2 A3 (II) R1 is defined as A under a^) or a2) , R2 denotes hydrogen or methyl, R3 denotes hydrogen or (Ci-Ce) -alkyl, preferably (Ci-C«) -alkyl, which is optionally monosubstituted by amino, substituted amino, hydroxyl, carbamoyl, guanidino, substituted guanidino, ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-ni trophenyl, 4-methoxypheny1, 4-hydroxyphenyl, phtalimido, 4-imidazolyl, 3-indolyl, 2- thienil, 3- thienil, 2- pyridyl, 3- pyridyl or cyclohexyl, where substituted amino stands for a compound -NH-A- and substituted guanidino stands for a compound -NH-C (NH) -NH-A, in which A is defined as under ai) or a2); B stands for a basie amino acid in the L- or D-con-figuration, which may be substituted in the side chain; c stands for a compound of the formula II la or Illb G' -G' -Gly G' -NH- (CH2) n-C0 (Illa) (Illb) in which

G' independently of one another denotes a radical of the formula IV

R4 R5 0 1 1 R N - CH - C (IV) in which R4 and Rs together with the atoms carxying them form a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms, and n is 2 to 8; E stands for the radical of an aromatic amino acid; F independently of one another denotes the radical of a neutral, acidic or basie, aliphatic or aromatic amino acid which may be substituted in the side Chain, or stands for a direct bond;

(D)-Tic denotes the radical of the formula V

G is as defined above for G' or denotes a direct bond: F' is as defined above for F,denotes a radical -NH- (CH2)n-, with n = 2 to 8, or, if G does not denote a direct bond, can stand for a direct bond, and I is -0H, -NH2 or -NHC2HS, K denotes the radical -NH-(CH2)x-CO- with x = 1-4 or stands for a direct bond, and M is as defined for F, and their physiologically tolerable salts. A peptide of the formula I as elaimed in elaim 1, in which

B denotes Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homoarginine radical, where in each casre the amino or guanidino group of the side chain may be sub- LV 10720 -J·- stituted by A as described under ai) or a2) in claim 1; E stands for the radical of an aromatic amino acid in the L- or D-configuration, which contains 6 to 14 carbon atoms in the aryl moiety as ring members, such as phenylalanine which is optionally substi-tuted by halogen in the 2-, 3- or 4-position, tyrosine, 0-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphtylalanine; F' ‘ denotes the radical of a basie amino acid in the L-or D-configuration, such as Arg or Lys, where the guanidino group or amino group of the side chain may be replaced by A as described under ai) or a2) in claim 1, or denotes a radical -NH- (CH2) n- with n = 2 to 8 and K stands for the radical -NH- (CHa)x-CO- with x = 2-4 or denotes a direct bond. A peptide of the formula I as elaimed in claim 1 or 2 in which B denotes Arg, Om or Lys, where the guanidino group or the amino group of the side chain is unsubsti-tuted or may be substituted by (Ci-C8)-alkanoyl, (C7-Cu) -aryloyl, (C3-C9) -heteroaryloyl, (Ci-C8) -alkylsul- fonyl or (C«-Ci2) -arylsulfonyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals may optionally be substituted, as described under a2) , with 1, 2, 3 or 4 identical or different radicals, E denotes phenylalanine, 2-chlorophenylalanine, 3- chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4- fluorophenylalanine, tyrosine, 0-methyltyrosine or β-(2-thienyl)alanine; -ί- Κ stands for a direct bond and M stands for a direct bond. 4. A peptide of the formula I as claimed in any one of claims 1 to 3 in which A denotes hydrogen, (D)- or (L)-H-Arg, (D) - or (L)-H-Lys or (D) - or (L)-H-Om; B denotes Arg, Om or Lys, where the guanidino group or the amino group of the side Chain may be sub-stituted by hydrogen/ (Ci-Ce) -alkanoyl, (C7-C13) - aryloyl, (C3-C9) -heteroaryloyl, (Cj-Ca) -alkylsulfonyl or (C6-Cx2)-arylsulfonyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals may optionally be substituted with 1, 2, 3 or 4 identi-cal or different radicals from the series comprising methyl, methoxy and halogen, C denotes Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly E denotes Phe or Thia F denotes Ser, Hser, Lys, Leu, Vai, Nle, Ile or Thr K stands for a direct bond M stands for a direct bond G stands for the radical of a heterocyclic ring system of the formula IV, where the radicals of the hetero- cycles pyrrolidine (A) / piperidine (B) / tetrahydro-isoquinoline (C) / cis- and trans-decahydroisoquino-line (D) ; cis-endo-octahydroindole (E), cis-exo-octaghydroindole (E), trans-octahydroindole (E), cis-endo-, cis-exo-, trans-octahydrocyclopentano[b]pyr-role, (F) or hydroxyproline (V) are preferred. LV 10720 -f- F' denote Arg and I stands for OH. 5. The preparation of a peptide of the formula ī as claimed in any one of the claims 1 to 4, which oanprises a) reacting a fragment having a C-terminal free car-boxyl group or its activated derivative with an appropriate fragment having an N-teminal free amino group or b) synthesizing the peptide stepvd.se, optionally splitting off one or more protective groups tsmp-orarily introduoed for the protection of other functions in the ccmpound obtained acoording to (a) or (b) and optionally converting the canpounds of the formula I thus obtained into their physiologically tolerable salt. 6. Use of a peptide of the formula I as claimed in any one of claims 1 to 4 as a medicament. 7. Use of a peptide of the formula I as claimed in any one of claims 1 to 4 for manufacturing of a medicament providing for the treatment of pathological States which are mediated, caused or supported by bradykinin-related peptides. 8. A pharmaceutical aģent oontaining a peptide of the formula I as claimed in any one of claims 1 to 4. LV 10720

Abstract of the disclosure:

Peptides having bradykinin antagonist action Peptides of the formula I A-B-C-E-F-K- (D)-Tic-G-M-F'-I (I) in which A stands for hydrogen, alkyl, alkanoyl, alkoxy-carbonyl, alkylsulfonyl, cycloalkyl/ aryl, arylsulfonyl, heteroaryl or an amino acid which may optionally be substituted, B is a basie amino acid, C denotes a di-peptide or tripeptide, E stands for the radical of an aroraatic amino acid, F independently of one another denotes an amino acid which is optionally substituted in the side chain or a direct bond, G is an amino acid, F' is as defined for F, -NH-(CH2)2.e or may optionally denote a direct bond, I is -0H, -NH2 or -NHC2H3 and K denotes a radical -NH-(CH2or stands for a direct bond, have bradykinin antagonist action. Their therapeutic utility ineludes ali pathological States which are mediatēd, caused or supported by bradykinin and bradykinin-related peptides. The peptides of the formula I are prepared by knovm methods of peptide synthesis.

Claims (8)

A peptide of formula (I): ABCEFK- (D) -Tic-G-M-P-I (I) wherein: Air a1): hydrogen, C 1-4 alkyl, C 1-6. C 1-8 alkanoyl, C 1-8 alkoxycarbonyl, C 1-4 alkylsulfonyl, and in these groups 1-3 hydrogen atoms may be substituted with 1-3 identical or different substituents: carboxyl, amino, C 1-4 alkyl , C 1-4 alkylamino, hydroxy, C 1-4 alkoxy, halogen, (C 1-4 alkyl) 2N-, carbamoyl, sulfamoyl, C 1-4 alkoxycarbonyl, C 6-12 aryl, substituted with C 6-10 aryl. - (1-4C) alkyl; 1 or one hydrogen atom substituted with a substituent: C 1-4 -cycloalkyl, C 1-4 -alkylsulfonyl, C 1-4 -alkylsulfinyl, C 1-4 -alkylsulfonyl, C 6-12 -aryl substituted C 1-6 -alkylsulfinyl, C6-12-aryloxy, C3-9-heteroaryl, C3g-heteroaryloxy, and 1-2 hydrogen atoms are replaced by 1-2 substituents: carboxyl, amino, C1-4alkylamino, hydroxy, C1-4alkoxy, halogen , (C 1-6 alkyl, N, carbamoyl, sulfamoyl, C 1-4 alkoxycarbonyl, C 6-12 aryl, C 6-12 alkyl substituted with C 6-12 aryl; C 3-8 cycloalkyl, carbamoyl which may have a nitrogen at C an alkyl or C 6-12 aryl group, a C 6-12 aryl group, a C 7-18 arylsulphonyl group, a C 6-12 arylsulfonyl group, a C 1-8 heteroaryl group, a C 2-8 arylsulfonyl group, the substituents a 1 and a 2 mentioned above, the heteroaryl may be replaced with 1-4 identical or different substituents from the group: carboxyl, amino, nitro, C 1-4 alkyl, C 1-4 alkylamino, hydroxy, C 1-4 alkoxy, halogen, cyano, C 1-4 alkyl (C 1-4 alkyl); N, carbamoyl, sulfamoyl, C 1-4 alkoxycarbonyl; or is also a substituent of formula (II) R 2 R 3 9 R 1 - N -OH - C - (II) wherein: R 1 has the meaning given to substituents a 1 and a 2; R 2 is hydrogen or methyl; R 3 is hydrogen or C 1-4 -alkyl, especially C 1-4 -alkyl, which may be substituted with one: amino, substituted amino, hydroxy, carbamoyl, guanidine, substituted guanidine, phenoxy, mercapto, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimide, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, pyridyl, 3-pyridyl, 3-pyridyl -NH-A- and substituted guanidine denote the compound -NH-C (= NH) -NH-A, where A has the meanings given to the substituents a1 and a, B is a basic amino acid of the L- or D- configuration which may be substituted in the side string; 3 C is a group of formula (IIIa) or (IIIb): G '-G'-Gly (IIIa) G' -NH- (CH 2) n -CO (IIIb) wherein G ', independently of one another, may be a residue of the formula (IV): P 1 P 5 9 - N-CH-C- (IV) wherein R 4 and R 5 together with the atoms to which they are attached may form a heterocyclic ring having 1 to 3 rings having 2 to 15 atoms; n = 2-8; E is an aromatic amino acid residue; F independently of one another is a residue of a neutral, acidic or basic aliphatic or aromatic amino acid which may be substituted in a side chain or a single bond; (D) -Tic is a residue of formula (V): G has the same meaning as G 'or a simple bond; F 'has the same meaning as F, or the group _NH- (CH2) n-, where n = 2-8, or, if G is not a single bond, may represent a single bond; I is -OH, -NH 2 or -NHC 2 H 5; K is -NH- (CH 2) x -CO-, where x = 1 -4, or represents a single bond; M has the same meaning as F; as well as physiologically acceptable salts thereof. 2. The peptide of formula (I) according to claim 1, wherein: B is Arg, Lys, Orn, 2,4-diaminobutyryl or L-homoarginine residue, wherein the side chain amino group or guanidine group may be replaced by substituents A having the meaning corresponds to the values of a1 and sr at point 1; E 10720 E is an aromatic L- or D-amino acid residue having 6 to 14 carbon atoms in the aryl group, such as phenylalanine which may be substituted by a halogen at the 2-, 3- or 4-position, tyrosine.O-methyl tyrosine, 2-thienylalanine, 2-pyridylalanine, naphthylalanine; F is a basic L- or D-amino acid residue, such as an arginine or lysine residue, and the side chain amino or Da or guanidine group may be replaced by a substituent A having the meanings of 'a1 and a2 in point 1; or -NH- (CH 2) n -, where n = 2-8; K is -NH- (CH 2) x -CO- where x = 2-4, or an represents a single bond. The peptide of formula (I) according to claim 1 or 2, wherein: B is a residue of Arg, Lys or Om, wherein the side chain amino group or guanidine group may be substituted by a C 1-4 alkanoyl group, a C 7,13 aryl aryl group. C 1 -C 8 -heteroaryl, C 1 -C 12 -alkylsulfonyl, C 8 -C 12 -arylsulfonyl, wherein heteroaryl, aroyl, arylsulfonyl, aryl and heteroaryloyl may be substituted at substituents a 2 with 1 to 4 substituents; E is a residue of phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, O-methyl tyrosine, p- (2-thienyl) alanine; K is a simple link; M is a simple link. A peptide of formula (I) according to any one of the preceding claims wherein: A is hydrogen, (D) - or (L) -H-Arg, (D) - or (L) -H-Lys, (D) - or (L) -H-Om; B is a residue of Arg, Lys or Om, wherein the side chain amino group or guanidine group may be substituted by a C 1-4 alkanoyl group, a C 1-4 aryloyl group, a C 1-8 heteroaryloyl group, a C 1-8 alkylsulfonyl group, a C 1-6 arylsulfonyl group. -the group, including heteroaryl, aroyl, arylsulfonyl, aryl and heteroaryl, may be substituted with 1-4 identical or different substituents: methyl, methoxy, halogen; 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; 5 K is a simple link; M is a simple link; G is a heterocyclic residue of formula (IV), particularly preferably a residue containing pyrrolidine (Δ), piperidine (fi), tetrahydroisoquinoline (C), cis- or trans-decahydroisoquinoline (D), cis-endo-octahydroindole (E). ), a heterocyclic system of cis-exo-octahydroindole (E), trans-octahydroindole (E), cis-endo, cis-exo-trans-octahydrocyclopentano [b] pyrrole (E) or hydroxyproline (V); F is Arg; I and Otf. A process for preparing a peptide of formula (I) according to any one of the preceding claims, characterized in that: a) the free C-terminal carboxyl moiety, or an activated derivative thereof, is treated with the corresponding N-terminal free amino moiety; or b) sequentially constructing the peptide and, if necessary, cleaving the protecting groups used to protect one or the other functional group in the peptide obtained by option a) or b) and converting the compound of formula I thus obtained into a physiologically acceptable salt thereof. The peptide of formula (I) according to any one of claims 1-4. for use as a therapeutic agent. A peptide of formula (I) according to any one of claims 1-4. for the manufacture of a medicament for the treatment of pathological conditions induced, maintained or promoted by bradykinin or related peptides. 8. A pharmaceutical composition comprising a peptide of formula (I) according to any one of claims 1-4. point. 6th