SK279315B6 - Peptides having antagonizing bradykinin effects and method of producing said peptides - Google Patents

Abstract

Peptides of the formula (I) in which A is hydrogen, alkyl, alkanoyl, alkoxycarbonyl, alkylsulphonyl, cycloalkyl, aryl, arylsulphonyl, heteroaryl or the residual of an amino acid, each of which can optionally be substituted; B is the residual of a basic amino acid; C is the residual of a di- or tripeptide; E is the residual 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 the residual of an amino acid; F' is defined as F and it can be -NH-(CH2)2-8 or optionally a direct bond; I is -OH, -NH2 or -NHC2H5; 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

Technical field

The present invention relates to novel peptides that antagonize the effects of bradykinin as well as a process for their production.

BACKGROUND OF THE INVENTION

Peptides antagonizing the effects of bradykinin are described in WO 86/07263, wherein, among these peptides, L-Pro at position 7 of the bradykinin peptide hormone or other bradykinin analogues is replaced by a D-amino acid such as D-Phe, D-Thi, D-Pal, CDF, D-NaI, MDY, D-Phg, D-His, D-Trp, D-Tyr, D-hPhe, D-Val, D-Ala, D-His, D-Ile, D-Leu, and DOMT.

SUMMARY OF THE INVENTION The object of the invention was to find novel active peptides which antagonize the action of bradykinin.

SUMMARY OF THE INVENTION

This task was solved by finding new peptides of formula (I)

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

A is a1) a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkanoyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 1 to 8 carbon atoms in the alkoxy moiety or an alkylsulfonyl group having 1 to 8 carbon atoms, , 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or 3 of the same or different radicals selected from the group consisting of carboxy, amino, (C 1 -C 4) alkyl, (C 1 -C 4) alkylamino, hydroxy, (C 1 -C 4) C 1 -C 4, halogen, C 1 -C 4 dialkylamino, carbamoyl, sulfamoyl, C 1 -C 4 alkoxy, C 6 -C 12 aryl and arylalkyl (C 6 -C 12) aryl and (C 1 -C 5) alkyl;

or wherein in each case one hydrogen atom is optionally replaced by a radical selected from the group consisting of C 3 -C 8 cycloalkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulphinyl, C 6 -C 4 arylalkylsulfonyl (C a-Cry a) aryl group having 1 to 4 carbon atoms in the alkyl moiety, arylalkylsulphinyl having 6 to 12 carbon atoms in the aryl moiety having 1 to 4 carbon atoms in the alkyl moiety, an aryloxy group having 6 to 12 carbon atoms, a heteroaryl group having 3 to 9 carbon atoms and heteroaryloxy of 3 to 9 carbon atoms; and 1 or 2 hydrogen atoms are optionally replaced with 1 or 2 of the same or different radicals selected from the group consisting of carboxy, amino, (C 1 -C 4) alkylamino, hydroxy, (C 1 -C 4) alkoxy, halogen, dialkylamino C 1 -C 4 alkyl, carbamoyl, sulfamoyl, C 1 -C 4 alkoxycarbonyl, C 6 -C 12 aryl and C 6 -C 12 arylalkyl and C 1 -C 4 arylalkyl 5 carbon atoms in the alkyl moiety;

a2) a C 3 -C 8 cycloalkyl group, a carbamoyl group optionally substituted on a nitrogen atom with a C 1 -C 6 alkyl group or a C 6 -C 12 aryl group;

(C až-Cry) aryl, (C až-Croy a) aryl group, (C až-C a a) arylsulfonyl, (Ci-C hetero) heteroaryl or (C až-C hetero) heteroaroyl group, with the radicals defined in (a1) and (a2) are in each case aryl, heteroaryl, aroyl, arylsulfonyl and heteroaroyl, optionally substituted with 1, 2, 3 or 4 of the same or different radicals selected from the group consisting of carboxy, amino, nitro, alkylamino (C 4-C 4), hydroxy, (C až-C alky) alkyl, (C až-C alko) alkoxy, halogen, cyano, (C až-C dial) dialkylamino, carbamoyl, sulfamoyl and alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety; or a3) rest of formula (Π)

R ¹ -N-CH-C (II) _{'2' 3} ¹¹

R ² R ³ O where

R ¹ has the meanings as A as defined in paragraphs al) or a2),

R ² is H or methyl;

R ³ is hydrogen or C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl optionally mono-substituted with amino, substituted with amino, hydroxy, carboxy, carbamoyl, guanidino, guanidino, ureido, mercapto, mercapto, mercapto, mercapto, mercapto, mercapto, mercapto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl a 2-pyridyl group, a 3-pyridyl group or a cyclohexyl group, the substituted amino group being -NH-A and the substituted guanidino group being -NH-C (NH) -NH-A, wherein A is as defined in paragraphs a1) or a2);

B represents a basic amino acid in the L- or D-configuration, which is optionally substituted in the side chain, C represents a group of formula (IIIa) or (IIIb)

G’-G’-Gly- (Bla)

-G'-NH- (CH ₂ ) _n -CO- (IV) in which

G 'is independently a group of formula (IV)

R ⁴ R ⁵ O

II ^| ( ^{| V} > N - CH - C where

SK 279315-6

R ⁴ and R ⁵ together with the atoms bearing these radicals 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 aromatic amino acid residue,

F is independently of any other neutral, acidic or basic, aliphatic or aromatic amino acid optionally substituted in the side chain or is a direct bond, (D) -Tic means a radical of formula (V)

E F

G has the same meaning as G 'defined or represents a direct link,

F 'has the same meaning as F, further denotes the group -NH- (CH 2) _h -, where n is a number from 2 to 8, or when G is not a direct bond, F' or a direct bond,

I is -OH, -NH ₂ or -NHC ₂ H 5, K is -NII-CH 1, I-CO-, wherein x is 1 to 4 or is a direct bond and M has the same meaning as F and i their physiologically tolerated salts.

Unless otherwise stated, the abbreviation for the amino acid residue without any indication of the stereochemistry means the L-form residue (cf. Schroder, Lubke, The Peptides, Vol. I, New York, 1965, pp. XXIII, Houben-Weyl, Methoden der organischen Chemie, Vol XV / 1 and 2, Stuttgart 1974), such as:

Aaad, Abu, Gamma Abu, Abz, 2Abz, __Aca, Ah, Acp,

Apt, Apt, Aib, Aib, Aib, A11, Aaa, Aaa, Ala, Alg, A11, Ama, Amt, Ape, Apm, Apr, Asn, Asp, Asu, Aze, Bai, Bph, Can, Cit Dad, dpa, dpa, dpa, dpa, dpa, dpa, dta, dpa, dpa, dlu, dlu, hlu, hlu, hlu, hlu, hlu, hlu, hlu, hlu, hlu, hlu , hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Len, Leu, Lsg, Lys, Lys, Lys, Lys, Met, Mim, Min, nArg, No Nva, Oly, Om, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, BetaThi, Thr, Thy , Thx, Tia, Tie, Trly, Tria, Tyr, Val.

As the radical of the heterocyclic ring system of formula (IV), a heterocycle radical selected from the group of the following heterocyclic radicals is in particular: pyrrolidine (A), piperidine (B), tetrahydroisoquinoline (C), decahydroisoquinoline (D), octahydroindole (B), 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 [2.2.2] octane) -2,3-pyrrolidine] (L), 2-azatricyclo [4.3.0.1 ^6,9 ] decane (M), decahydrocyclohepta [b] pyrrole (N), octahydroisoindole (O), octahydrocyclopenta [c] pyrrole (P), 2,3,3a, 4,5,7a-hexahydroindole (Q) , tetrahydrothiazole (R), 2-azabicyclo [3.1.0] hexane (S), isoxazolidine (T), pyrazolidine (U), hydroxyproline (V), all of which are optionally substituted.

Heterocyclic compounds corresponding to the abovementioned residues are known from e.g.

US-A 4,344,949, US-A 4,374,847, US-A 4,350,704, EP-A 50,800, EP-A 31,741, EP-A 51,020, EP-A 49,658, EP-A 49,605 , EP-A 29,488, EP-A 46,953, EP-A 52,870, EP-A 271,865,

DE-A 32 26 768, DE-A 31 51 690, DE-A 32 10 496, DE-A 32 11 397, DE-A 32 11 676, DE-A 32 27 055, DE-A 32 42 151, DE -A 32 46 503 and DA 32 46 757.

Furthermore, some of these heterocyclic compounds are described in DE-A 38 18 850.3.

Unless expressly stated otherwise in an individual case, the alkyl group may be straight or branched. Correspondingly, this applies to groups derived from an alkyl group such as an alkoxy group, an aralkyl group or an alkanoyl group.

The C 6 -C 12 aryl group is preferably phenyl, naphthyl or biphenylyl. Correspondingly, this applies to groups which are derived from an aryl group, such as an aryloxy, aralkyl or aroyl group.

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

Suitable salts are, in particular, alkali metal or alkaline earth metal salts, salts with physiologically tolerable amines and salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, filmaric acid, citric acid, tartaric acid, acetic acid.

Preferred are peptides of formula (I) wherein B is Arg, Lys, Om, 2,4-diarninobutyroyl or an L-homoarginine residue, wherein the amino or guanidino side chain group is optionally substituted with A as defined in (a1) or (a2) , B represents an aromatic amino acid residue in the L- or D-configuration, which contains 6 to 14 carbon atoms in the aryl moiety as ring members such as phenylalanine optionally substituted in the 2, 3 or 4 position by halogen, tyrosine, O- methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine,

F 'is a basic amino acid residue in the L- or D-configuration, such as Arg or Lys, wherein the guanidino or amino side chain group is optionally substituted with A as described in (a1) or (a2) or is -NH- (CH2 ₎ ) _n - in which n is a number from 2 to 8,

K is -NH- (CH ₂ ) x -CO-, wherein x is from 2 to 4 or is a direct bond.

Particularly preferred are the peptides of formula (I) in which

SK 279315-6

B is Arg, Om or Lys, wherein the guanidino or amino group of the side chain is unsubstituted or optionally substituted with C 1 -C 8 alkanoyl, C 7 -C 13 aroyl, C 3 -C 9 heteroaroyl, alkylsulfonyl (C 1 -C 8) or (C 6 -C 12) -sulfonyl group, wherein the aryl, heteroaryl, aroyl, arylsulfonyl, and heteroaroyl groups are optionally substituted with 1, 2, 3 or 4 with the same or different radicals listed in (a1) , E represents a residue of phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, O-methyltyrosine or beta- (2-thienyl) alanine,

K represents a direct bond and

M represents a direct bond.

Particularly particularly preferred are peptides of formula (I) wherein:

A represents a hydrogen atom, (D) - or (L) -H-Arg, (D) - or (L) -H-Lys or (D) - or (L) -H-Om,

B is Arg, Om or Lys, wherein the guanidino or amino group of the side chain is optionally substituted with hydrogen, C 1 -C 8 alkanoyl, C 7 -C 13 aroyl, C 3 -C 9 heteroaroyl, alkylsulfonyl (C 1 -C 8) or (C 6 -C 12) arylsulfonyl group, wherein the aryl, heteroaryl, aroyl, arylsulfonyl and heteroaroyl radicals are optionally substituted with 1, 2, 3 or 4 of the same or different substituents selected from the group consisting of it consists of a methyl group, a methoxy group and a halogen atom,

C stands for Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly

E stands for Phe or Thia,

F stands for Ser, Hser, Lys, Leu, Val, No, Ile or Thr,

K stands for direct bond,

M is a direct bond,

G is a radical of the heterocyclic ring system of formula (IV), with preference given to the following heterocycles: pyrrolidine (A), piperidine (B), tetrahydroisoquinoline (C), cis- and trans-decahydroisoquinoline (D), cis-endo-octahydroindole ( E), cis-cis-octahydroindole (E), transoctaliydroindole (E), cis-endo-, cis-exo-, trans-octahydrocyclopentano [b] pyrrole (F) or hydroxyproline (V), F 'is Arg,

I is hydroxy.

Examples of particularly preferred peptides of formula (I) include:

H- (D) -Arg-Arg-Pro-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH H- (D) -Arg-Arg-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 invention further relates to a process for the production of peptides of the general formula (I) which comprises:

(a) reacting a fragment with a free carboxyl group on a terminal carbon atom or an activated derivative thereof with a corresponding fragment with a free amino group on a terminal nitrogen atom, or

b) exposing the peptide sequentially, optionally removing one or more protecting groups temporarily introduced to protect other functions in the compound obtained under a) or b), and optionally converting the thus obtained compounds of formula I to their physiologically tolerable salts.

The peptides of the present invention are prepared according to generally known methods of peptide chemistry. See, for example, Houben-Weyl, Methoden der organischen Chemie, Vol. 15/2. Preferably, solid phase synthesis is used as described, for example, by B. Merrifeldel, J. Am. Chem. Soc. 85, 2149 (1963) or R. C. Sheppard, Lnt. J. Peptide Protein Res. 21, 118 (1983) or other equivalent known methods are used. As alpha-amino protecting groups, urethane protecting groups such as tert-butyloxycarbonyl protecting groups (Boe) or fluorenylmethoxycarbonyl protecting groups (Fmoc) are used. If it is necessary to prevent side reactions or to synthesize special peptides, additional functional groups in the side chain of the amino acids are protected by suitable protecting groups (pores, for example T. W. Greene, "Protective Groups in Organic Synthesis").

Arg (Tos), Arg (Mts), Arg (PMtr), 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), LysiBoc), Met (O), SerfBzl), Ser (But), Thr (Bzl), Thr (But), Trp (Mts), Trp (CHO), Tyr (Br-Z), TyyBzl) or Tyr (But).

Solid phase synthesis begins at the end of the terminal carbon atom peptide by coupling the protected amino acid to the corresponding resin. Starting materials of this type can be obtained by coupling the protected amino acid with a polystyrene or polyacrylamide resin, modified with a chloromethyl group, a hydroxymethyl group, a benzhydrylamino group (BHA) or a methylbenzhydrylamino group (MBHA) via an ester or amide bond. Resins used as carriers are commercially available. BHA and MBHA-modified resins are generally used when the synthesized peptide is to contain a free amido group at the terminal carbon atom. If the peptide is to contain a secondary amido group at the terminal atom, resins modified with a chloromethyl or hydroxymethyl group are used, and cleavage is carried out using the corresponding amines. If, for example, ethylamide is to be obtained, the peptide can be cleaved from the corresponding resin using ethylamine, and the side chain protecting groups are cleaved in the next step using other suitable reagents. If tert-butyl side chain amino acid protecting groups are to be retained in the peptide, then the synthesis is performed using a fluorophenylmethyloxycarbonyl protecting group to temporarily block the alpha-amino group of the amino acid using the methodology described, for example, by R. C. Sheppard, J. Chem. Soc. Chem. Comm. 1982, 587, wherein the guanidine function of arginine is protected by protonation using pyridinium perchlorate and the protection of other amino acids functionalized in the side chain is performed by catalytic hydrogenation (cf. A. Fclix et al., J. Org. Chem. 13, 4194 (1978) or sodium). in liquid ammonia (W: Roberts, J. Am. Chem. Soc. 76, 6203 (1954)) of the cleavable benzyl protecting groups.

After cleavage of the amino protecting group of the amino acid coupled to the resin with a suitable reagent, such as trifluoroacetic acid in methylene chloride for the Boc-protecting group or 20% piperidine solution in dimethylformamide for the Fmoc-protecting group, the protected amino acids are sequentially coupled. Intermediate peptide resins with a protected terminal nitrogen atom are unblocked with the described reagents prior to coupling with the following amino acid derivative.

All possible activating agents used in the synthesis of peptides can be used as coupling agents, cf., for example, Houben-Weyl, Methoden der organischen Chemie, Vol. 15/2, but especially carbodiimides such as N, N'-dicyclohexylcarbodiimide, N, N'-diisopropylcarbodiimide or N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide. Coupling can be carried out directly by the addition of an amino acid derivative using an activating agent and optionally a racemization suppressant such as 1-hydroxybenzotriazole (HOBt) (W. Kbnig, R. Geiger, Chem. Ber. 103, 708 (1970)) or 3- hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) (W. Konig, R. Geiger, Chem. Ber. 103, 2054 (1970)) to form a resin or also by pre-activation of an amino acid derivative in the form of a symmetrical anhydride; The HOBt- or HOObt-ester and the thus-obtained solution of the activated substance in a suitable solvent are then added to the coupling resin.

Coupling or activation of amino acid derivatives with any of the activating agents mentioned may be carried out in dimethylformamide, N-methylpyrrolidone or methylene chloride or in a mixture of the solvents mentioned. The activated amino acid derivative is usually used at 1.5 to 4 times the equivalent amount. In cases where incomplete coupling occurs, the coupling reaction is repeated without previously requiring unblocking of the alpha-amino acid of the peptide resin necessary for coupling the next amino acid.

The successful course of the coupling reaction can be controlled by a ninhydrin reaction as described, for example, by E. Kaiser et al., Anal. Biochem. 34, 595 (1970). Synthesis can also be automated, for example, using an automated peptide synthesizer (Model 430 A, manufactured by Applied Biosystems), using either synthesis programs designed by the instrument manufacturer or synthesis programs developed by the user himself. The latter method is mainly used with Fmoc-protected amino acid derivatives.

After the peptide has been synthesized as described above, the peptide can be cleaved from the resin with reagents such as liquid hydrogen fluoride (preferably for peptides produced by the Boe method) or trifluoroacetic acid (preferably for peptides synthesized by the Fmoc method). These agents cleave not only the peptide from the resin, but also other side chain protecting groups of the amino acid derivatives. In this way, in addition, the BHA-modified and MBHA-modified peptides are obtained in the free acid form. When using BHA or MBHA-modified resins, a peptide is obtained in the form of the acid amide when cleaved with hydrogen fluoride or trifluoromethanesulfonic acid. Further processes for the production of peptide amides are described in German patent applications P 37 11 866.8 and P 37 43 620.1. Here, the amide peptide is cleaved from the resin by treatment with moderately strong acids, which are commonly used in peptide synthesis (e.g., trifluoroacetic acid), using cationic substances such as phenol, cresol, thiocresol, anisole, thioanisole, ethanedithiol, dimethylsulfide. or similar cationic substances customary in solid phase synthesis, individually or in a mixture of two or more of these auxiliary agents. The trifluoroacetic acid can also be used in this case diluted with a suitable solvent, such as methylene chloride.

If tert-butyl or benzyl protecting groups are to be retained in the side chains of the peptides, cleavage of the peptide synthesized on a particularly modified carrier resin is carried out with 1% trifluoroacetic acid in methylene chloride, as described, for example, by R. C. Sheppard, J. Chem. Soc., Chem. Comm. 1982, 587. If individual tertiary butyl or benzyl side chain protecting groups are to be retained, suitable combinations of synthesis and cleavage methods are used.

Similarly, the modified resins described by Sheppard are used to synthesize peptides with an amide moiety or an omega-amino- or omega-guaaidinalkyl moiety at the terminal carbon atom. After synthesis, the peptide, which is completely protected in the side chain, is cleaved from the resin and then reacted by classical synthesis solution in solution with the corresponding amine, optionally with omegaaminoalkylamine or omega-guanidinoalkylamine, and any other functional groups present may be temporarily protected in a known manner.

Another method for producing peptides with an omega-anunoalkyl moiety is described in German patent application P 36 35 670.0.

The peptides of the present invention are preferably synthesized using a solid phase technique according to two general methods of protecting groups.

One of these methods is synthesis performed using an Applied Biosystems Model 430A Automatic Peptide Synthesizer using Boe and Fmoc protecting groups, respectively, to temporarily protect the alpha-amino group.

When using a Boe protecting group, synthesis cycles that are pre-programmed by the instrument manufacturer are used for synthesis.

Synthesis of peptides with a free carboxyl group at the terminal containing a terminal carbon atom is performed using a Boc-amino-functionalized 4- (hydroxymethyl) phenylacetamido-methylpolystyrene resin (RB Merrifield, J. Org. Chem 43, 2845 (1978)) (Applied Biosystems) . MBHA resin is used for the production of peptidamides, i. j. product of the same company.

N, N'-dicyclohexylcarbodiimide or Ν, Ν'-diisopropylcarbodiimide serve as activating agents. Activation is carried out in the form of symmetrical anhydride, HOBt ester or HOObt ester in methylene chloride, in mixtures of methylene chloride and dimethylformamide or N-methylpyrrolidine. For coupling, 2-4 equivalents of activated amino acid derivative are used. In cases where the coupling was incomplete, the reaction was repeated.

When using the Fmoc protecting group to temporarily protect the alpha-amino group, their own synthesis programs are used for synthesis using an automated peptide synthesizer (Model 430A from Applied Biosystems). The synthesis is carried out on a resin modified with a p-benzyloxybenzyl alcohol residue (cf., for example, S. Wang, J. Am. Chem. Soc. 95, 1328 (1973) (manufactured by Bachem) which has been esterified according to a known method (E. Atherton et al. (JCS Chem. Comm., 1981, 336) using the corresponding amino acid HOBt- or HOObt-ester amino acid derivatives are activated directly in the amino acid containers provided by the instrument manufacturer by adding a solution of diisopropylcarbodiimide in dimethylformamide to a pre-weighed mixture of amino acid derivative and HOBt or HOObt. The OObt-esters of Fmocamino acid can also be used as described in the European patent application No. 87107634.5 The cleavage of the Fmoc protecting group is carried out with a 20% solution of piperidine in dimethyl.

276 Fonnamide in the reaction vessel. The excess reactive amino acid derivative used is 1.5 to 2.5 equivalents. If the coupling is incomplete, it is repeated as in the Boe protecting group method.

The peptides of the invention, individually or in combination, have an antagonistic effect of bradykinin. This effect can be demonstrated by tests in various models (cf., for example, Handbook of Exp. Pharmacol. Vol. 25, Springer Verlag, 1970, pp. 53-55), such as isolated rat uterus, guinea pig ileum, or isolated guinea pig lung arteries .

In order to test the peptides of the invention on isolated Arteria pulmonalis, guinea pigs (Dunkin Hartely) weighing 400-450 g are sacrificed by a wound to the back of the nape.

The rib cage is opened and the Arteria pulmonalis is carefully removed. The surrounding tissue is carefully removed and the Arteria pulmonalis is spirally cut at 45 °.

The arterial strips, 2.5 cm long and 3-4 mm wide, are fixed in a 10 ml organ bath filled with Ringer's solution. Composition of the solution in mmol / liter:

NaCl 154

KCI5,6

CaCl ₂ 1.9

_NaHCO3 2.4 glukóza5,0.

A solution containing 95% oxygen and 5% carbon dioxide was bubbled through the solution and heated to 37 ° C. The pH is 7.4, the preload on the artery strips is 1.0 g.

Isotonic contraction changes are captured using a lever and HF-modem (Hugo Sachs) and registered with a compensating recorder (BEC, Goetz MetrawattSE 460).

After one hour of equilibration, the experiment is started. Then, when the artery strips reach their maximum sensitivity against 2 x 10 ^-7 mol / liter bradykinin - bradykinin causes contraction of the artery strips - the peptide is allowed to act for 10 minutes at doses of 5 x 10 ⁸ to 1 x 10 ^-5 moles / liter and the re-addition of bradykinin compares the decrease in the effect of bradykinin compared to the control.

Peptides are used at 1 x 10 ^-5 to 1 x 10 ^-3 mol / liter to determine the partial agonist effect.

_IC50 values calculated from dose-response curves for the various peptides of the invention are shown in Table 1 below.

Table 1 Compound IC ₅₀ (mol)

4.6 x1ο ⁶ H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Ihia-Arg-OH 2.1 x10 ⁶

H-pj-Arg-Atg-Pro-Hyp-CH-Phe-Sa'rpyTic-Hie-Arg-OH 1.2 x 10 ' ⁵

H- (D) -Arg-Arg-Hyp-Ito-Gly-Ph & Gl < (D) Tic-Hie-Aig-OH 2 A x 10 ⁵

H- (D) -Arg-Arg-ft-O-Hyp-C3y-Phe-Ser- (D) -Tic-Flie-Aig (Mtr} -OH 2.5 x ¹⁰ -5t- (D) -Arg-Aig-Hyp- Pn> Cay-Phe-Ser- (D) -Tic-Fro-Arg-OH 2.5 x 10 ^-7

H- (DyArg-Arg-Hyp-Prc > -Gy-71iia-Sa- (pyTi > Pro-Aig-OH 1.9 x 10 ' ⁷⁾

PyArg H-Arg-Pro-Hyp-C3y-Thia-Ser- (D) .Tio Alg-Aoc-OH-5.6 x I H ^p

H- (D) -Arg-Aig-Hyp-Pn > Gly-Thia-Ser-6-Ala- (D) -Tic-Aoc-AtgOH 1.7 x1ο ⁶

H-pj-Arg-Atg-Hyp-PiO-Gly-Thia-Sa-Gly-4-tic-Aoc-Arg-OH 3.9 x 10 ⁷

Hp) -Aig-Aig-Hyp-PiO-Giy-'Iliia-Gly- (P) -Tio (DJ _J ) -Oic, Arg-OH 3.2 x 10 ⁷

H- (D) -Arg- (D) -Arg-Hyp-fto-CBy-Ihia-Ser-Dppi-Aoc-Arg-OH 4.8 x 10 ⁷

H- (D) -Arg-Aig-1-glyp-Pro-dy-Ihia-Ser- (D) -Tio-Thio-Arg-CH 1.7 x 10 ⁷

H- (D > Aig-Aig-phto-Hyp-CIy-THa. ^ - ^} Thio-Aoc> Atg-OH 1.1 x 10 ^R

I I- (DyArg-Aig-iyo-Hyp <Hy-HK> Ser- (D) -Tic-Aoc-Alg-OH 4.6 x 10 ⁸

H- (pyTyr-Arg-lVoHyp-Qly-Ihia-S- (D) -TILE-Aoc-Alg-OH 6.2 x 10 ⁸

H- {DyArg-Arg-Pro-Hyp-Gty-Ihia-Ser- (D) -Tic- (DyOic ₁ Arg-OH 2.6 x 10 ⁵ H- (D) -Arg-Aig-Pn> -Hyp <Hy-'núa-Serre ') - Thio-Oio-Atg-OH 5.4 x 10 ⁹

H- (D) -Arg-Lys-n-Hyp-Gly-Hie-Ser- (D) -Tio.Aoc-Aig-OH 3 J x 10 ⁷

H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (P) -Tic-OC-Arg-OH 6.8 x 10 '

H- (D> Arg-Arg <NO ₂ > -nO-Hyp-Gly-Phe-Ser- (D) -Tio-Aoc-Aig-OH 6.4 x 10 ⁸

H- (D> Arg-Aig-Ifeft) GV-THa-Ser- (DyTic-Oic-A ^ -OH 4.2 x Go '

H- (D) -Arg-Prc> -Hyp-Gly-Fhe-Ser- (P) -Tic-Oic-Aig-OH 3.4 x 10 ⁷

H-Atg- (Tos) -Pro-Hyp <ly-Phe-Ser <D> ric-Oic-Arg-OH 3.0 x 10 ⁸

H-Aig- (Tos) -Pn> Hyp-Gly-Ser-11iia (D) .TioOio AigOH 1.8 ^xlO-8

The therapeutic uses of the peptides of the invention include all pathological conditions that are mediated, caused or supported by bradykinin and bradykinin-related peptides. This area includes, but is not limited to, injuries such as wounds, burns, rashes; eiytenes, swelling, tonsillitis, arthritis, asthma, allergies, rhinitis, shock, inflammation, low blood pressure, pain, itching and alteration of sperm motility.

The invention also relates to the use of the peptides of formula (1) as medicaments and pharmaceutical preparations containing them.

The pharmaceutical preparations contain an effective amount of the active compound of formula (I) - alone or in combination - together with an inorganic or organic pharmaceutically acceptable carrier.

Administration can be effected enterally, parenterally such as subcutaneously, intramuscularly or intravenously, sublingually, epicutaneously, nasally, rectally, intravaginally, intrabucally or by inhalation. The dose of the active ingredient depends on the species of warm-blooded individual, body weight, age and method of administration.

The pharmaceutical compositions of the present invention are prepared by known dissolution, mixing, granulation or auctioning techniques.

For oral or mucosal administration, the active compounds are admixed with conventional excipients, such as carriers, stabilizers or diluents, and converted into suitable dosage forms, such as tablets, dragees, push-fit capsules, by conventional methods. , aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch. The preparation can be carried out in both dry and wet granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil and fish oil.

The topical preparation may be formulated as an aqueous or oily solution, lotion, emulsion or jelly, ointment or ointment, or, if possible, sprayed, whereby adhesion may optionally be improved by the addition of a polymer.

In order to prepare an intranasal dosage form, the compounds are admixed with conventional additives such as stabilizers or inert diluents, and the mixture is worked up by conventional methods into a suitable dosage form such as aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. . Chelating agents, ethylenediamine-N, N, N ', N'-tetraacetic acid, citric acid, tartaric acid or salts thereof can be added to aqueous intranasal formulations. The application of nasal solutions can be carried out by means of a dispenser spray or in the form of nasal drops with the addition of a viscosity-increasing portion, optionally in the form of a nasal gel or in the form of a nasal cream.

For inhalation administration, nebulizers or pressurized gas may be used in suitable packaging using inert carrier gases.

For intravenous, subcutaneous, epicutaneous or intradermal administration, the active substances or their physiologically tolerable salts are, where appropriate, used with auxiliaries customary for these pharmaceutical purposes, for example isotonation or pH adjustment, as well as co-solvents, emulsifiers or other auxiliaries for solutions, suspensions or emulsions.

SK 279315-6

Given the short half-lives of some of the medicaments described in body fluids, the use of delayed-release injectable preparations is of importance. As dosage forms, for example, oil suspensions of crystals, microcapsules, sticks or implants can be used, and implants can be obtained using tissue-compatible polymers, in particular biodegradable polymers such as polylactic acid-polyglycolic acid copolymers or human albumin.

A suitable dosage range for topical and inhalation dosage forms is 0.01 to 5 mg / ml for solutions and 0.01 to 10 mg / kg for systemic dosage forms.

Abbreviations used:

The abbreviations used for amino acids correspond to the usual three-letter code in peptide chemistry as described in Europe. J. Biochem. 138, 9 (1984). Other abbreviations used are listed below: Acm acetamidomethyl ε-Ahx ε-aminohexanoyl

Aoc cis, endo-2-azabicyclo [3.3.0] octane-3S-carbonyl Boe tert-butyloxycarbonyl

But tert-butyl

Bzl benzyl

C1-Z4-chlorobenzyloxycarbonyl

DMF dimethylformamide

Dnp 2,4-dinitrophenyl

Fmoc 9-fluorenylmethyloxycarbonyl

Me methyl

4-Methyl 4-methylbenzyl

Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl

Mts mesitylene-2-sulfonyl

NMP N-methylpyrrolidine

Oic cis-endo-octahydroindole-2-carbonyl

Ac acetyl

Opr isoxazolidin-3-ylcarbonyl

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl

TFA trifluoroacetic acid

Tcs 4-methylphenylsulfonyl

Thia 2-thienylalanyl

These 1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl

Trt trityl

The following examples illustrate preferred methods for solid phase synthesis of peptides of the invention without limiting the invention in any way.

The following amino acid derivatives are used: I'moc-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-beta-Ala-OH, Fmoc-Oic-OH.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-ArgOH was sequentially exposed using an automatic peptide synthesizer (Model 430, manufactured by Applied Biosystems) using a protective method. Fmoc group on a resin modified with p-benzyloxybenzyl alcohol and esterified with Fmoc-Arg (Mtr) -OH (manufactured by Novabiochem) (loading about 0.5 mmol / g resin). In the process, 1 g of said resin is used and the synthesis is carried out using a synthesis program modified for the Fmoc method.

1mol of an amino acid derivative having a free carboxyl group was weighed into the autosynthetic containers together with 0.95 mmol of HOObt. Pre-activation of these amino acids is carried out directly in the containers by dissolving in 4 ml of dimethylformamide and adding 2 ml of a 0.5 M solution of diisopropylcarbodiimide in dimethylformamide.

The HOObt esters of the other amino acids are dissolved in 6 ml of N-methylpyrrolidine and then, like the amino acids previously activated in situ, are coupled to a resin which has previously been unblocked with a 20% solution of piperidine in dimethylformamide. Upon completion of the synthesis, the peptide is cleaved while removing the side chain protecting groups with trifluoroacetic acid using thioanisole and ethanedithiol as a cation-binding agent from the resin. The residue obtained after removal of trifluoroacetic acid is digested several times with ethyl acetate and then centrifuged. The remaining residue is chromatographed on an ion exchanger (Sephadex LH 20) using 10% acetic acid. Fractions containing pure peptide were pooled and freeze-dried.

FAB-MS: 1294 (M + H).

In an analogous manner to that described in Example 1, the peptides set forth in Examples 2 to 24 are prepared and purified.

Example 2 II- (L) -Arg-Arg-Hyp-Pro-Gly-Phe- (D) -Ser- (D) -Tic-Phe-Arg-OH

FAB-MS: 1294 (M + H)

Example 3 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH Mass Spectrum (FAB): 1 306 (M + H)

Example 4 H- (D) -Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-Arg-OH Mass Spectrum (FAB): 1,294 (M + H)

Example H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Gln- (D) -Tic-Phe-Arg-OH Mass Spectrum (FAB): 1,335 (M + H)

Example 6 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Pro-Arg-OH Mass Spectrum (FAB): 1244 (M + H)

Example 7 H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Trp- (D) -Tic-Phe-Arg-OH Mass Spectrum (FAB): 1,393 (M + H)

Example 8 H- (D) -Arg-Arg-Hyp-Pro-Giy-Thia-Ser- (D) -Tic-Pro-Arg-OH Mass Spectrum (FAB): 1250 (M + H)

Example 9 H- (D) -Arg-Arg 4 +} β-Fto-Gly-γ- (D) -Am- (D) -Tic-lhia- / VgOH Mass Spectrum (FAB): 1333 (M + H)

Example 10 H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Opr- (D) -THI-Thia-Arg-OH Mass Spectrum (FAB): 1,301 (M + H)

SK 279315-6

Example 11

H-P) -Aig-Arg-Gly-Hyp4ho-thia (D) -GB-phenyl)) - Tic-Thia-Arg-OH

FAB-MS: 1347 (M and H)

Example 12

H- (D) -Arg-Arg-HypBro-Giy-Thia-Ser-Gly- (D) -Tic-PiD-Aig-OH Mass Spectrum (FAB): 1,307 (M + H)

Example 13

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

FAB-MS: 1241 (M + H)

Example 14

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

FAB-MS: 1,397 (M + H)

Example 15

H- (D) -Arg-Pro-Arg41yp-Gly-Thi-Ser-Ala-be1ay (D) -Tic-Pro-Arg-OH

FAB-MS: 1321 (M + H)

Example 16

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D) -Tic-Pro-Arg-OH Mass Spectrum (FAB): 1,220 (M + H)

Example 17

H- (D) -Arg-Arg-Aoc-Pro-Gly-Thia-Ser- (D) -Tic-Thia-ArgOH Mass Spectrum (FAB): 1330 (M + H)

Example 18

H- (D) -Arg-Arg-Pro-Aoc-Gly-Thia-Ser- (D) -Tic-Thia-Arg-OH Mass Spectrum (FAB): 1330 (M + H)

Example 19

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-ArgOH Mass Spectrum (FAB): 1,290 (M + H)

Example 20

H- (D) -Arg-Arg-Opr-Pro-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH Mass Spectrum (FAB): 1,236 (M + H)

Example 21

H- (D) -Arg-Arg-Pro-Opr-Gly-Thia-Ser- (D) -Tic-Pro-Arg-OH Mass Spectrum (FAB): 1,236 (M + H)

Example 22

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Opr-Arg-OH Mass Spectrum (FAB): 1,252 (M + H)

Example 23

H- (D) -Aig- (D) -Aig-Hyp-Pro-Gly-1hia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,290 (M + H)

Example 24

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,290 (M + H)

Examples 25 to 27

H-d9) -Ag-Arg (Mrr) Bro-Hyp-Gly-Phe-Ser- (D) -Tic4beT.Arg-OII and

H- (D) -Ag-Arg4ho-Hyp-Gfy-Phe-Ser- (D > Tic-Phe-Aig (MTr) -OH; and

1 '- {1'Frg-Arg (T 1 -Tr) 4 Y -Ryp- (1b / 4Tx> Sa'-R 3) -Ti> HK'T' \ rg (1'r) - (1 H) was prepared in an analogous manner to that described in Example 1, wherein the cleavage of the side chain and peptide protecting groups from the resin is carried out with trifluoroacetic acid for a limited period of 30 minutes at room temperature. Under such selected conditions, only a negligible cleavage of the Mtr protecting group on arginine occurs. The partially unblocked peptides are separated and purified by chromatography using reverse phase material.

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

FAB-MS: 1 506 (M + H)

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

FAB-MS: 1718 (M + H)

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

FAB-MS: 1 506 (M + H)

The peptides set forth in the following Examples 28 to 31 are prepared and purified in an analogous manner to that described in Examples 25 to 27.

Example 28 H- (D) -Arg 7Arg (Mtr) -Hyp-Pro-Gly-11ia-Ser- (D) -Tic 4 hO-ArgOH Mass Spectrum (FAB): 1,462 (M + H)

Example 29

H- (9) -Arg-Arg-Hyp-Pro-Gly-Thia-Scr- (D) -Tic-Pro-Atg (Mtr) OH Mass Spectrum (FAB): 1,462 (M + H)

Example 30

H-f) - ArgTArg (Mtr) -Hyp-Pro-Gly-Tliia-Ser- (D) -Tk> Pro-Fhe-OH Mass Spectrum (FAB): 1 453 (M + H)

Example 31

H- (D) -Arg-Arg (Mtr) -Hyp-Prc-Gly-1-Hia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1 502 (M + H)

Example 32 H-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH) 4-NH 2

Peptide synthesis is carried out on 1 g of aminomethyl-modified resin which has additionally been modified by the group described in EP-A 264 802

Fmoc-NH- (CH.,), - NH-CO-O-CH, -C-CO CH CO -.- ^X C - C using OObt esters of Fmoc-amino acid by using an automatic peptide synthesizer (Model 430A, manufactured by Applied Biosystems) and by synthesis programs that have been modified in their own way. To this end, 1 mmole of the corresponding amino acid derivative is weighed into containers supplied by the manufacturer and then Fmoc-Arg (Mtr) -OH, Fmoc-Hyp-OH and Fmoc- (D) -Tic-OH together with 0.95 are weighed into the containers. mmól HOObt. The in situ pre-activation of these amino acids is carried out directly in the containers by dissolving in 4 ml of dimethylformamide and adding 2 ml of a 0.55 M solution of diisopropylcarbodiimide in dimethylformamide. The HOObt esters of the other amino acids are dissolved in 6 ml of N-methylpyrrolidine and then coupled to a resin that has been unblocked beforehand with 20% pyridine in dimethylformamide, in the same manner as pre-activated in situ activated amino acids, whereby in situ activated amino acids are coupled twice. Upon completion of the synthesis, the peptide 4-aminobutylamide is cleaved from the resin while removing the side chain protecting groups by treatment with trifluoroacetic acid containing thioanisole and m-cresol as a binding agent.

276 cations. The residue obtained after removal of trifluoroacetic acid is digested several times with ethyl acetate and then centrifuged. The remaining crude peptide was chromatographed on a resin (Sephadex G25) using 1 N acetic acid as eluent. Fractions containing pure peptide were pooled and freeze-dried.

In an analogous manner to that described in Example 32, the compounds of Examples 33 to 35 were prepared.

Example 33

HD-Arg-Arg-IIyp-Pro-Gly-Phe-Ser- (D) -Tic-I ^: he-NH- (CH) ₂ 4 < H ₂ Mass Spectrum (FAB): 1 208 (M + H)

Example 34

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

FAB-MS: 1152 (M + H)

Example 35

HOOC- (CH _{2) 2} -CO- (D) -Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Phe-NH- (CH _{2) 4} -NH ₂

FAB-MS: 1 308 (M + H)

The peptides described in Examples 36-161 were synthesized by the method described in Example 1.

Example 36

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

FAB-MS: 1 307 (M + H)

Example 37

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

FAB-MS: 1 307 (M + H)

Example 38

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (P) -Tic-PiO-Phe-OH Mass Spectrum (FAB): 1,241 (M + H)

Example 39

H- (D) -Arg-Arg-β-Pto-Gly-11a-Ser-beta-A] α- (D) -Tic-Aoc-AigOH Mass Spectrum (FAB): 1,361 (M + H)

Example 40

H- (D) -Arg-Arg4-Hyp-Gty-Li-Ser-bda -, lla - (D) -Tic-Aoo-ArgOH Mass Spectrum (FAB): 1,361 (M + H)

Example 41

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

FAB-MS: 1,397 (M + H)

Example 42

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

FAB-MS: 1,397 (M + H)

Example 43

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Gly- (D) -Tic-Aoc-ArgOH Mass Spectrum (FAB): 1,260 (M + H)

Example 44

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,260 (M + H)

Example 45

H- (D) -Arg- (D) -Aig-Hyp-Pro-Gly-Ser-Ihiala (D) -tk-Aoc-Aig-OH

FAB-MS: 1290 (M + H)

Example 46

Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1290 (M + H)

Example 47

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH Mass Spectrum (FAB): 1,312 (M + H)

Example 48

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Tic-Arg-OH Mass Spectrum (FAB): 1,312 (M + H)

Example 49

H- (D) -Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,274 (M + H)

Example 50

H- (D) -Arg-Arg-Hyp-Pro-Gly-Thia- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,203 (M + H)

Example 51

H- (D) -Arg-Arg-Hyp-Pro-Gly-Aoc-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,274 (M + H)

Example 52

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

FAB-MS: 1274 (M + H)

Example 53

H-2 O-Arg-Arg-Pro-Hyp-Gl-1-Thia-beta-Ala-1D-Tic-Aoc-Aig-OH Mass Spectrum (FAB): 1,274 (M + H)

Example 54

H- (D) -Arg-Arg-Hyp-Pro-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,252 (M + H)

Example 55

H- (D) -Arg-Arg-Pro-Hyp-Gly-Asp-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,252 (M + H)

Example 56

H- (D) -Arg-Arg-Hyp-Pro-Gly-Trp-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,323.7 (M + H)

Example 57

H- (D) -Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,297.7 (M + H)

Example 58

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

FAB-MS: 1 304.6 (M + H)

Example 59

H- (D) -Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,304.6 (M + H)

Example 60

II- (D) -Arg-Arg-Pro-Pro-Gly-Bua-Scr- (D) -Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,289 (M + H)

Example 61

H- (D) -Arg-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,262 (M + H)

SK 279315-6

Example 62

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

FAB-MS: 1276 (M + H)

Example 63

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

FAB-MS: 1260 (M + H)

Example 64

H-β-Arg-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,298 (M + H)

Example 65

H- (D) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-O-ArgOH Mass Spectrum (FAB): 1,298 (M + H)

Example 66

H- (D) -Arg-Arg-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH Mass Spectrum (FAB): 1282 (M + H)

Example 67

H - () - Aig-Arg (NQ) -PtO-Hyp4jly-Ftie-Ser- (p) -Tic-Aoc-Aig-OH Mass Spectrum (FAB): 1 329.7 (M + H)

Example 68

H-4>) - Aig-Arg (NQ) -Pro-Hyp-Gly-Hie-Ser- (D} -TK-Oic-AigOH Mass Spectrum (FAB): 1,343 (M + H)

Example 69 [[- (Dj-Argi-Ci-Pro-Pro-Il-Phe-Scr-Il-Tic-Oic-Arg-OII) Mass Spectrum (FAB): 1327 (M + H)]

Example 70

H4P) -Aig-Arg (Q) -PiO-Pro4Jly-1Hi-Ser- (D) -Tic-Oic-Arg-OH Mass Spectrum (FAB): 1333 (M + H)

Example 71

H - (I) -Ag-Arg (NQ) 4Yo-Hyp-Gly-Ihia-Ser- (D) -TK-Ok-Arg-JH FAB: 1,349 (M + H)

Example 72

H-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,302 (M + H)

Example 73

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

FAB-MS: 1142 (M + H)

Example 74

H-Lys-f-CO-NH-QHi-Pro-Hyp-Gly-Hie-Ser-D-Ti-Oic-ArgOH Mass Spectrum (FAB): 1,233 (M + H)

Example 75

H-Arg (Tos) -Pro-Hyp-Gly-Pli-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,296 (M + H)

Example 76

H-Lys- (nicotinoyl) -Pro-Hyp-Gly-Plie-Ser-D-Tic-Oic-Ajg-OH Mass Spectrum (FAB): 1,219 (M + H)

Example 77

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

Example 78

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

FAB-MS: 1324 (M + H)

Example 79

H-D-Arg-Arg (Tos) -Pio-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1438 (M + H)

Example 80

H-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,302 (M + H)

Example 81

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

FAB-MS: 1142 (M + H)

Example 82

H-Lys (-CO-NH-QH5) 41yp-Pro-Gly-Fhe-Ser-D-Tic-C18-Aig-OH Mass Spectrum (FAB): 1,233 (M + H)

Example 83

H-Arg (Tos) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,296 (M + H)

Example 84

H-Lys (nicotinoyl) -Hyp-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,219 (M + H)

Example 85

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

Example 86

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

Example 87

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

Example 88

H-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,286 (M + H)

Example 89

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

FAB-MS: 1 126 (M + H)

Example 90

H-Lys (-C (NH ₃ kH ₃ ) -Pro-PiO-Gly-Phe-Ser-D-Tic) ic-Arg-OH Mass Spectrum (FAB): 1 217 (M + H)

Example 91

H-Arg (Tos) -Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1280 (M + II)

Example 92

H-Lys (nicotinoyl) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-ArgOH Mass Spectrum (FAB): 1 203 (M + H)

Example 93

H-Arg (Tos) -Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,266 (M + H)

Example 94

Ac-Arg (Tos) -Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,308 (M + H)

SK 279315-6

Example 95

H-D-Arg-Argfros) -Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH

FAB-MS: 1422 (M + H)

Example 96

H-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1148 (M + H)

Example 97

H-Lys / GO-NH-QHs-Pro-Hyp-Gly-Thia-Ser-D-TicOic-ArgOH Mass Spectrum (FAB): 1,239 (M + H)

Example 98

H-Lys (iiicotnioyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,225 (M + H)

Example 99

H-Arg (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,288 (M + H)

Example 100

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

Example 101

H-D-Arg-Arg (Tos) -ITo-Hyp-Gly-Thia-Ser-D-Tic-Aoc-Arg-On Mass Spectrum (FAB): 1,444 (M + H)

Example 102

H-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1148 (M + H)

Example 103

I-Lys (GO-NH-QHs) -lyp-Pro-Gly-Tliia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,239 (M + H)

Example 104

H-Lys (nicotinoyl) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,225 (M + H)

Example 105

H-Arg (Tos) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,288 (M + H)

Example 106

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

Example 107

H-D-Arg-Arg (Tos) -Hyp-Pro-Gly-Ihia-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1440 (M + H)

Example 108

H-LysCGO-NH-Cyd 3 -fto-Pro-Gly-Thia-Ser-D-Tic-Oic-x'-rOH Mass Spectrum (FAB): 1,225 (M + H)

Example 109

H-Lys (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1 209 (M + H)

Example 110

H-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,272 (M + H)

Example 111

Ac-Arg (Tos) -Pro-Gly-Tliia-Ser-D-Tic-Aoc-Arg-OII Mass Spectrum (FAB): 1,314 (M + H)

Example 112

H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,428 (M + H)

Example 113

H-D-ArgBysinicotinoyl-Bro-ProGly -rhia-Ser-D-Tic-Oic-AigOH Mass Spectrum (FAB): 1,365 (M + H)

Example 114

H-D-Arg-Lys (-CO-NH-C 1 H 5) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1,379 (M + H)

Example 115

H-D-Arg-Arg (Tos) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-ArgOH Mass Spectrum (FAB): 1,442 (M + H)

Example 116

H-Lys-Lys- (nicotinoyl) -Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-ArgOH Mass Spectrum (FAB): 1,337 (M + H)

Example 117

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

FAB-MS: 1351 (M + H)

Example 118

H-Lys-Arg (T axis) -Pro-Pro-Gly-Thia-Ser-D-Ti-Oic-Arg-OH Mass Spectrum (FAB): 1414 (M + H)

Example 119

H-D-AigUysinicotinoyl-Pto-Hyp-Gly-Ilyia-Ser-Mic-Oic-ArgGH Mass Spectrum (FAB): 1,381 (M + H)

Example 120

H-D-Arg-Lys

FAB-MS: 1,395 (M + H)

Example 121

H-D-Arg-Arg (Tos) -PiO-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,458 (M + H)

Example 122

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

FAB-MS: 1,367 (M + H)

Example 123

H-Lys-Lys (nicotinoyl) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-AigOH Mass Spectrum (FAB): 1,353 (M + H)

Example 124

H-Lys-Aig (Tos) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1430 (M + H)

Example 125

H-D-Arg-Lys (nicotnioyl) -Pro-Pro-Gly-Phe-Ser-D-Tit > Oic-Arg-OH Mass Spectrum (FAB): 1,359 (M + H)

Example 126

H IAArg-lysine-NH-CO-Cf.H'O-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1373 (M + H)

Example 127

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

SK 279315-6

FAB-MS: 1436 (M + H)

Example 128

H-Lys-Lys (nicotinoyl) -Pro-Gly-PTO-Phe-Ser-D-Tic-Oic-Aig-OH

FAB-MS: 1331 (M + H)

Example 129

H-Lys-Lys (-CO-NH-C6H5) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1345 (M + H)

Example 130

H-Lys-Arg (Tos) -Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,408 (M + H)

Example 131

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

FAB-MS: 1375 (M + H)

Example 132

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

FAB-MS: 1,389 (M + H)

Example 133

H-D-Arg-Arg (Tos) -fto-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,452 (M + H)

Example 134

H-Lys-Lys (Nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1,347 (M + H)

Example 135

H-Lys-Lys (-CO-NH-C _with H5) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1,361 (M + H)

Example 136

H-Lys-Arg (Tos) -Pro-Hyp-Gty-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1424 (M + H)

Example 137

H-D-Arg-Orn (Nicotinoyl) -Pro-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1351 (M + H)

Example 138

H-D-Arg-OMI-CO-NH-CsHsj-PIO-Pro-Gly-Thi-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1428 (M + H)

Example 139

H-LysOm (nicotinoyl) -Pro-Pto-Giy-Thia-Ser-D-Tic-Oic-ArgOH Mass Spectrum (FAB): 1,323 (M + H)

Example 140

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

FAB-MS: 1337 (M + H)

Example 141

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

FAB-MS: 1,367 (M + H)

Example 142

HD-Arg-Orn (-CO-NH-C _s H ₅₎ -Pro-Hyp-Gly-Ser Niia ^{r-D-Tic-Oic-Arg-OH}

FAB-MS: 1,381 (M + H)

Example 143

H-Lys-Om (nicotinoyl) -Pro-Hvp-Gly-Thia-Ser-D-TicOic-Aig-OH Mass Spectrum (FAB): 1,339 (M + H)

Example 144

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

FAB-MS: 1353 (M + H)

Example 145

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

FAB-MS: 1345 (M + H)

Example 146

H-D-Arg-OMI-CO-NH-CjHjj-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1359 (M + H)

Example 147

H-Lys-Oni (nicotinoyl) -Pro-Pro-Gly-Ser-Plie-D-Tic-Oic-Arg-OH

FAB-MS: 1317 (M + H)

Example 148

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

FAB-MS: 1331 (M + H)

Example 149

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

FAB-MS: 1,361 (M + H)

Example 150

HD-Arg-Om (-CO-NH-C ₆ II ₅ ) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1375 (M + H)

Example 151

H-Lys-Om (nicotinoyl) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Aig-OH Mass Spectrum (FAB): 1333 (M + H)

Example 152

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

FAB-MS: 1347 (M + H)

Example 153

H-Lys-Lys-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1218 (M + H)

Example 154

H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,234 (M + H)

Example 155

H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,234 (M + H)

Example 156

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

FAB-MS: 1,212 (M + H)

Example 157

H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser- (D) -Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,228 (M + H)

Example 158

H-Lys-Lys-Pro-Gly-Thia-Scr- (D) -Tic-Oic-Arg-OH Mass Spectrum (FAB): 1232 (M + H)

Example 159

H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D) -Tic-Oic-Arg-OH Mass Spectrum (FAB): 1248 (M + H)

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

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

The compounds of Examples 162 to 164 are prepared in an analogous manner to that described in Example 32 using the resin described in EP-A 322 348 with the following structure:

c = o

I

KH ^0B 2 (polystyrene)

Example 162

II-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2

FAB-MS: 1283 (M-II)

Example 163

_{HD-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2}

FAB-MS: 1283 (M + H)

Example 164

H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2

FAB-MS: 1267 (M + H)

The peptides of Examples 165-194 can also be obtained by the method of Example 1.

Example 165

H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH

FAB-MS: 1267 (M + H)

Example 166

H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH

FAB-MS: 1284 (M + H)

Example 167

H-D-Arg-Lys (Z) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,390.7 (M + H)

Example 168

H-D-Arg-Lys-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,256.7 (M + H)

Example 169

H-D-Arg-Ser (Rha) -Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1,361 (M + H)

Example 170

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

FAB-MS: 1345 (M + H)

Example 171

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

FAB-MS: 1650.7 (M + H)

Example 172

H-D-Arg-Arg-Hyp-Pro-Gly-thia-Ser-D-Tic-D-Aoc-Arg-OH Mass Spectrum (FAB): 1290 (M + H)

Example 173

H-D-Arg-Arg-Pro-Hyp-Gly-Iia-Ser-D-Tic-D-Oic-Arg-OH Mass Spectrum (FAB): 1 304.7 (M + H)

Example 174

H-D-Arg-Arg-OP-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1 302.7 (M + H)

Example 175

H-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1 304.7 (M + H)

Example 176

4-hydroxyphenylpropionyl-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1 452.7 (M + H)

Example 177

H-D-Arg-D-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1 304.7 (M + H)

Example 178

H-D-Arg-Arg-D-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Aig-OH Mass Spectrum (FAB): 1 304.6 (M + H)

Example 179

H-D-Arg-Arg-Pro-Hyp-Gly-Tlu-Ser-D-Tic-Oic-D-Arg-OH Mass Spectrum (FAB): 1 304.9 (M + H)

Example 180

H-D-Arg-Arg-Pro-Hyp-Gly-D-Thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1 304.8 (M + H)

Example 181

H-D-Arg-Pro-Hyp-Gly-thia-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1148 (M + H)

Example 182

H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-OH Mass Spectrum (FAB): 1 147 (M + H)

SK 279315-6

Example 183 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-D-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1 304.7 (M + H)

Example 184 Ac-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH MS (FAB): 1 ^with 34 ^'9 (M + H)

Example 184 H-D-Arg-Arg (Mtr) -Hyp-Pro-Gly-Thia-Ser-D-Tic-Pro-Phe-OH Mass Spectrum (FAB): 1454.9 (M + H)

Example 185

H-D-Arg-Arg-Hyp-Pro-Gly-Thia-D-Tic-O-L-Oic-Arg-OH Mass Spectrum (FAB): 1,274 (M + H)

Example 186 H-D-Arg-Arg-Hyp-Pro-Gly-Thia-beta-Ala-D-Tic-Aoc-Arg-OH Mass Spectrum (FAB): 1 354.6 (M + H)

Example 187 H-D-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1142.5 (M-H)

Example 188 (4-benzoyl) oxyoxyacetyl-D-Arg-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1 542.6 (M + H)

Example 189 H - ((4-Benzoyl) benzoyl) -Lys-D-Arg-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH

FAB-MS: 1640.9 (M + H)

Example 190 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Cys-D-Tic-Oic-Arg-OH Mass Spectrum (FAB): 1320.7 (M + H)

Example 191 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic- (3a R, 7a S) Oic-Atg-OH Mass Spectrum (FAB): 1 304.7 (M + H)

EXAMPLE 192 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic- (3aS, 7aR) Oic-Arg-OH

FAB-MS: 1 304.7 (M + H)

Example 193 HD-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-NH ₂ Mass Spectrum (FAB): 1147.6 (M + H)

Example 194 H-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-OH

The peptide of Example 194 is obtained by the method of Example 1, but cleaved from the resin as follows:

The resin-bound resin is swelled for 10 minutes in a 1: 2 mixture of m-cresol and dichloromethane, using about 2 ml of mixture per g of resin, and then about 10 ml of trifluoroacetic acid per g of resin is added and stirring is continued. , 8 ml trimethylsilyl bromide per g resin. The mixture is left to react for 1.5 hours, then filtered using a glass suction and an ice-cold mixture of methyl ether and tert-butyl ether. The precipitated crude peptide is filtered off, washed with the same solvent and filtered off with suction to dryness. Then, the crude peptide is dissolved in water, the aqueous solution is extracted with ethyl acetate, and the 1RA 93 exchanger in acetate form is added. The ion exchanger is then filtered off with suction and washed with a little water. The filtrate was lyophilized and the crude acetate acetate obtained was chromatographed on a Sephadex LH 20 column using 10% acetic acid. The crude peptide fractions were pooled and lyophilized.

FAB-MS: 992.6 (M + H)

IC ₅₀ values calculated from dose-response curves for the various peptides of the invention are shown in Table 2 below.

Table 2

Example compound IC ₅₀ (mol) 1 4.6 x 10 ^-6 3 2.1 x 10 ^-6 4 L, 2 x 10 ^-5 5 2.4 x 10 ^-5 6 2.5 x 10 ' ⁷ 7 3.7 x 10 ^-5 8 1.9x10 ' ⁷ 9 4.6 x 10 ^-5 13 6.0 x 10 ^-5 19 3,4 x 10 ' ⁸ 23 4.8 x 10 ' ⁷ 24 1.1 x 10 ' ⁸ 27 2.5 x 10 ^-5 29 3.7 x 10 ⁷ 38 6.0 x 10 ^-5 39 1.7 x 10 ' ⁶ 44 3.9 x 10 ' ⁷ 45 4.8 x 10 ' ⁷ 47 1.7 x 10 ' ⁷ 48 9.5 x 10 ' ⁸ 54 8.9 x 10 ' ³ 56 8.0 x 10 ' ⁷ 57 6.2 x 10 ' ⁸ 58 2.6 x 10 ^-3 59 5.4 x 10 ' ⁹ 60 4.2 x 10 ' ⁹ 64 6.8 x 10 ' ⁹ 67 6.4 x 10 ' ⁸ 72 1.8 x 10 ^sec 73 3.0 x ^10.8 74 4.8 x 10 ' ⁸ 75 3.0 x ^10.8 76 3.2 x 10 ' ⁷ 77 7.0 x ^10.8 78 2.5 x 10 ' ⁷ 79 3.5 x 10 ' ⁸ 159 7.8 x ^10.8 162 7.2 x 10 ' ⁷ 165 3.0 x ^10.8 166 4.6 x ^10.8 167 2.8 x O ' ⁷ 168 3.2 x 10 ' ⁷

SK 279315-6

Continuation of Table 2

Example compound IC ₅₀ (mol) 169 2.0 x ^10.7 170 6.8 x ^10.6 171 5.0 x 10 ^-5 172 1.8 x 10 ' ⁶ 173 2.6 x 10 ^-5 174 1.3 x 10 ' ⁸ 175 1.7 x 10 ' ⁸ 176 3.6 x 10 ' ⁸ 177 1.1 x 10 ' ⁷ 178 1.3 x 10 ' ⁷ 179 1.8 x 10 ' ⁷ 180 1.8 x 10 ' ⁷ 181 2.4 x 10 ' ⁷ 182 2.9 x 10 ' ⁷ 183 8.0 x 10 ' ⁶ 184 2.3 x ^10.8 185 4.4 x 10 ' ⁶ 186 3.2 x 10 ' ⁷ 188 3.4 x 10 ' ⁷ 189 l, 6 x 10 ^-8 190 6.6 x 10 ' ⁹ 191 L, 2 x 10 ^-8 192 1.5 x 20 ' ⁷ 193 8.9 x 10 ' ⁸ 194 4.2 x 10 ' ⁸

PATENT CLAIMS

Claims (6)

PATENT CLAIMS 1. Peptides antagonizing the effects of bradykinin of formula (I) A-B-C-E-F-K- (D) -Tic-G-M-F'-I (D, where A represents a hydrogen atom, an alkanoyl or an alkoxycarbonyl group having from 1 to 8 carbon atoms in each case, optionally in which one of the hydrogen atoms is replaced by a carboxyl group or a radical of formula (II) R ¹ -N-CH-CO- (II), Wherein R ¹ and R ² are hydrogen and R ³ is C 1 -C 8 alkyl optionally substituted with hydroxyphenyl, amino or guanidine, B represents a basic amino acid in the L- or D- configuration, optionally substituted in the side chain, C is a compound of formula (IIa) G’-G’-Gly (Illa), where G ’independently represent the rest of the formula (TV) -N-CH-CO- (IV) I I R ⁴ R ⁵ wherein R ⁴ and R 5 together with the atoms to which they are attached form a heterocyclic mono-, bi- or tricyclic ring system of 2 to 15 carbon atoms, E stands for the aromatic amino acid residue, F represents a neutral, acidic or basic, aliphatic or aromatic amino acid residue in the L- or D- configuration, optionally substituted in the side chain, or F can be a direct chemical bond, (D) -Tic means a radical of formula (V) G has the same meaning as G ’or means a direct chemical bond, F 'is the same as F or can be -NH- (CH ₂ ) n, where n is an integer of 2 to 8, or if G is different from a direct bond, F' can be a direct bond, I represents a hydroxy group, an amino group or a group -nh-c ₂ h ₅ K is the radical -NH- _{(CH2) x} -CO- where x is 1 to 4, or a direct chemical bond, M has the same meaning as F as well as physiologically acceptable salts of these compounds. Peptides of formula (I) according to claim 1, characterized in that: A represents a hydrogen atom, a (C 1 -C 4) alkanoyl, a (C 1 -C 4) carboxyalkanoyl or a radical of formula (II) wherein R ¹ and R ² are hydrogen and R ³ is C 1 -C 4 alkyl carbon atoms, substituted with p-hydroxyphenyl, amino or guanidine, B is a basic amino acid in the L- or D- configuration of Arg, Lys and Om, optionally substituted in the side chain with substituents from Mtr, NCF, Tos, nicotinoyl or -CO-NH-C ₆ H ₅ , C is a compound of formula (IIIa) wherein G 'is independently the radical of formula (TV) and R ⁴ and R ⁵ form with the atoms to which they are attached a heterocyclic ring system from Pro, Hyp, Aoc and Opr, L represents the aromatic amino acid residue of the Phe, Thia and Trp groups, F is a residue of a neutral, acidic or basic, aliphatic or aromatic amino acid in the L- or D- configuration of Ser, Thia, Gln, Trp, Asn and Opr or a direct bond, (D) -Tic is a radical of formula (V), G is, like G ', a radical of formula (IV) wherein R ⁴ and R ⁵ together with the atoms to which they are attached form a heterocyclic ring system from Pro, Aoc, Opr, Oic and Tie or G represents a direct chemical bond . SK 279315-6 F 'represents Arg in the L- or D- configuration, optionally substituted in the Mtr side chain or -NH- (CH ₂ ). or when G has a meaning other than a direct bond, F 'may be a direct bond, I is hydroxy or amino, A represents a radical -NH- _{(CH2) x} -CO- where x = 1 or 2 and A is a direct bond and M is the residue of an aromatic amino acid from the group of Phe or Thia, or a direct bond, and physiologically acceptable salts of these acids. Peptides of formula (I) according to claim 1, characterized in that they are compounds of the group 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- (P) -Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH or H- (P) -Arg-Arg-Pro-Pro-Gly-Phe-Ser- (D) -Tic-Oic-Arg-OH, as well as the physiologically acceptable salts of these compounds. Peptides of formula (I) according to claim 1, characterized in that: A is hydrogen, C1 -C4 carboxyalkanoyl or a radical of formula (II) wherein R ^{@ 1} and R @ ² are hydrogen and R @ ³ is C1 -C4 alkyl substituted with guanidine, B represents the basic amino acid Arg in the L- or D- configuration, optionally substituted in the Mtr side chain, C represents a compound of formula (IIIa) in which G 'independently of one another is a radical of formula (IVa) R ⁴ and R ⁵ together with the atoms to which they are attached represent a heterocyclic ring system from the group Pro, Hyp, Aoc and Opr, E represents the residue of the aromatic amino acid Phe or Thia, F represents a residue of neutral, acidic or basic, aliphatic or aromatic amino acids in the L or D configuration of Ser, Thia, Gln, Trp, Asn and Opr, (D) -This means the remainder of formula (V), G is, like G ', a radical of formula (IV) in which R ⁴ and R ⁵ together with the atoms to which they are attached form a heterocyclic ring system from Pro, Aoc or Opr, or G can be a direct chemical bond, F 'is an amino acid Arg optionally substituted in the Mtr side chain or -NH- (CH ₂ ) ₄ - or, if G has a different meaning from a direct chemical bond, F' may be a direct bond, I is hydroxy or amino, A represents a radical -NH- _{(CH2) x} -CO- where x = 1 or 2 and A is a direct chemical bond, M is the residue of an aromatic amino acid from the group of Phe or Thia, or a direct bond, such as and physiologically acceptable salts thereof. Peptides of general formula (I) according to claim 1, characterized in that they are compounds of the group H- (D) -Arg-Arg-Hyp-Pro-Gly-Aoc-Ser- (D) -Tic-AOc-Arg -OH, H- (D) -Arg-Arg-Pro-Hyp-Gly-Asp-Ser- (D) -Tic-AOc-Arg-OH or H- (D) -Arg-Arg-Pro-Hyp-Gly -Asp-Ser- (D) -Tic-AOc-Arg-OH or a physiologically acceptable salt thereof. A process for the production of the peptides of the general formula (I) according to claim 1, characterized in that it is: a) reacting a fragment with a free C-terminal carboxyl group or an activated derivative thereof with a corresponding fragment with a free N-terminal amino group, or b) the peptide is built up sequentially, whereupon one or more protecting groups temporarily introduced to protect other groups are optionally cleaved from the compound obtained in one of embodiments a) or b), and the compound of formula I thus obtained is optionally converted into its a physiologically acceptable salt.