CA1340667C

CA1340667C - Peptides having bradykinin antagonist action

Info

Publication number: CA1340667C
Application number: CA000607853A
Authority: CA
Inventors: Stephen Henke; Hiristo Anagnostopulos; Gerhard Breipohl; Jochen Knolle; Jens Stechl; Bernward Scholkens
Original assignee: Hoechst AG
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1988-11-24
Filing date: 1989-08-09
Publication date: 1999-07-20
Anticipated expiration: 2016-07-20
Also published as: CY2008022I2; AU612054B2; MX9203277A; EP0370453B1; NO177597B; ES2057071T3; DK384089D0; LU91499I2; PH31009A; CY2008022I1; DE122008000066I2; CZ490689A3; IE63490B1; EP0370453A2; JPH07121956B2; DK384089A; NO2008016I1; FI893738L; HK1006716A1; IL91298A

Abstract

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, alkoxycarbonyl, alkylsulfonyl, cycloalkyl, aryl, arylsulfonyl, heteroaryl or an amino acid which may optionally be substituted, B is a basic amino acid, C denotes a dipeptide or tripeptide, E stands for the radical of an aromatic 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)2-8 or may optionally denote a direct bond, I is -OH, -NH2 or -NHC2H5 and K denotes a radical -NH-(CH2)1-4,-CO- or stands for a direct bond, have bradykinin antagonist action. Their therapeutic utility includes all pathological states which are mediated, caused or supported by bradykinin and bradykinin-related peptides. The peptides of the formula I are prepared by known methods of peptide synthesis.

Description

1~~06~7 Description Peptides having bradykinin antagonist action The invention relates to novel peptides having bradykinin 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, D-Thi, D-Pal, CDF, D-Nal, ICY, 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.
This object is achieved by the peptides of the formula I
A-B-C-E-F-K- (D)-Tic-G-M-F'- I ( I )' in which A al) denotes hydrogen, ( C1-C8 ) -alkyl, (C,-C8)-alkanoyl, (Cl-C8)-alkoxycarbonyl or (Cl-C8)-alkylsulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or 3 identical or different radicals from the series comprising carboxyl, amino, ( C1-C, ) -alkyl , ( Cl-C~ ) -alkyl amino, hydroxyl, ( C1-C, ) -alkoxy, halogen, di- ( C1-C4 ) -alkyl amino, 13~~0~~;7 carbamoyl, sulfamoyl, (C1-C,)-alkoxycarbonyl, ( Cs-C12 ) -aryl and (Cs-C12)-aryl-(Cl-CS)-alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical from the series comprising ( C3-Cg ) -cyc loalkyl , ( C1-C, ) -alkylsul f onyl , (C1-C,)-alkylsulfinyl, ( Cs-C1Z ) -aryl- ( C1-C, ) -alkylsul f onyl , ( Cs-C12 ) -aryl- ( C1-C, ) -alkylsul finyl, ( Cs-Cia ) -aryloxy.
( C3-C9 ) -heteroaryl and ( C3-C9 ) -heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals from the series comprising carboxyl, amino, ( C1-C, ) -alkylamino, hydroxyl, ( C1-C, ) -alkoxy, halogen, di- ( C1-C, ) -alkyl amino, carbamoyl, sulfamoyl, ( C1-C, ) -alkoxycarbonyl , ( Cs-C12 ) -aryl and ( Cs-C1z) -aryl- ( C1-CS ) -alkyl, a2 ) denotes ( C3-Cs ) -cycloalkyl, carbamoyl, which may be optionally substituted on the nitrogen by ( C1-Cs ) -alkyl or ( Cs-C12 ) -aryl , ( Cs-Ciz ) -aryl .
( C,-C13 ) -aryloyl , ( Cs-C12 ) -arylsul fonyl , ( C3-C9 ) -heteroaryl , or ( C3-C9 ) -heteroaryloyl , where in the radicals defined under al) and a2) in each case aryl, heteroaryl, aryloyl, arylsulfonyl and - 3 - ~~~~~~7 heteroaryloyl is optionally substituted by 1, 2, 3 or 4 identical or different radicals from the series com-prising carboxyl, amino, nitro, ( C1-C4 ) -alkyl amino, hydroxyl, ( C1-C, ) -alkyl , ( C1-C, ) -alkoxy, halogen, cyano, di- ( C1-C, ) -alkyl amino, carbamoyl, sulfamoyl and ( C1-C, ) -alkoxycarbonyl , or a3) denotes a radical of the formula II

R1 - N - CH - C - (II) R1 is de f fined as A under al ) or a2 ) , RZ denotes hydrogen or methyl, R3 denotes hydrogen or (C1-C6)-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, 1~40b~7 4-hydroxyphenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 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 al ) or a2 ) ;
B stands for a basic 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 IIIa or IIIb G' - G' - G1 y G' - NH- ( CH2 ) n- CO
(IIIa) {IIIb) in which G' independently of one another denotes a radical of the formula IV

- N - CH - C - (IV) in which R' and RS 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 basic, 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
H O
w ~ ~ (v) N
G is as defined above for G' or denotes a direct bond;

1340~~~

F' is as defined for F, denotes a radical -NH-(CHZ)a-, with n = 2 to 8, or, if G does not denote a direct bond, can stand for a direct bond, and I is -OH, -NHZ or -NHCZHS, K denotes the radical -NH-(CHZ)~-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 otherwise, the abbreviation of an amino acid radical without a stereodescriptor stands for the radical in the L-form (compare Schroder, Liibke; The Peptides, Volume I, New York 1965, pages XXII-XXIII;
Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Volume XV/1 and 2, Stuttgart 1974), such as, for example, Aad, Abu, 7Abu, ABz, 2ABz, EAca, Ach, Acp, Adpd, Ahb, Aib, SAib, Ala, SAla, p Ala, Alg, AlI, Ama, 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, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hPhe, hero, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, dLys, p Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, SThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val.
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 (~); decahydroisoquinoline (D); octahydroindole (E);
octahydrocyclopenta[b]pyrrole (F); 2-aza-bicyclo[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[(bi-~~~oas~

cyclo[2.2.1]heptane)-2,3-pyrrolidine] (R); spiro[(bi-cyclo[2.2.2]octane)-2,3-pyrrolidine] (L); 2-azatricyclo-[4.3Ø16~9]decane (M); decahydrocyclohepta[b]pyrrole (N);
octahydroisoindole (O); octahydrocyclopenta[c]pyrrole (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); all of which may be optionally substituted.

_,_ >" c o _ ~- c o _ ~ I ~"_co _ ~-- co _ N H W Nw ~ Nw A H
A
~p_ ~~ ~.c0- H-N H N 0_ G
E F _ ~,-.cc- ~c0_ ~.co- ~.cc-N H
~R II I
J x CO- CO- CO- ~CD-J L I N I N IS
H IH ~ S
p- CO- ~ 0- ~ CO-i - N R ~I' N
o i p J , t Ho p~-CO- N CO- CO
~N
i t 1 V

13~0~~7 The heterocycles based on the abovementioned radicals are known, for example, from 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-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.
Some of these heterocycles are furthermore proposed in DE-A-3,818,850.3.
If not stated otherwise in the individual case, alkyl can be straight-chain or branched. The same applies to radicals derived therefrom such as alkoxy, aralkyl or alkanoyl.
(C6-ClZ)-Aryl preferably denotes 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, preferably for chlorine.
Possible 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, for example, HC1, HHr, H2SOw, H3P0" malefic acid, fumaric acid, citric acid, tartaric acid and acetic acid.
Preferred geptides 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 or guanidino group of the side chain may be sub-stituted by A as described under al) or a2);

- ?~340~~7 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 basic 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 al) or a2) , or denotes a radical -NH-(CHZ)n - with n = 2 to 8 and R stands for the radical -NH-(CHZ)=-CO- with x = 2-4 or denotes a direct bond.
Particularly preferred peptides of the formula I are those in which 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-CB ) -alkanoyl, ( C~-2 0 C13 ) -aryloyl , ( C3-C9 ) -heteroaryloyl , ( C1-Ce ) -alkylsul fonyl or (C6-C12)-arylsulfonyl, where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals may optionally be substituted, as described under az), 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 ~-(2-thienyl)alanine;
K stands for a direct bond and M stands for a direct bond 1340b67 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, 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-CB ) -alkanoyl, ( C~-C13 ) -aryloyl, (C3-C9)-heteroaryloyl, (C1-Ce)-alkylsulfonyl or ( C6-C12 ) -arylsul f onyl , 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, Val, Nle, Ile or Thr R 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 traps-decahydroisoquino-line (D); cis-endo-octahydroindole (E), cis-exo-octahydroindole (E), traps-octahydroindole (E), cis-endo-, cis-exo-, traps-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-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 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 known 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 known methods. Urethane protec-tive groups such as, for example, the tert-butyloxy-carbonyl(Boc) or fluorenylmethoxycarbonyl(Fmoc) protec-tive group are used as a-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 13~Q~~7 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(C1-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 materials 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 materials 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 wished 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 reagents. 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 a-amino group of the amino acid using the method described, for example, in R.C. Sheppard, J.Chem.Soc., Chem.Comm 1982, 587, the guanidino function of the arginine being protec-ted 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 liquid ammonia (W. Roberts, J.Am.Chem.Soc. 76, 6203 (1954)).
After splitting off the amino protective group of the amino acid coupled to the resin using a suitable reagent, such as, for example, trifluoroacetic acid in methylene chloride in the case of the Boc protective group or a 20$
strength solution of piperidine in dimethylformamide in the case of the F~noc protective group, the subsequently protected amino acids are successively coupled in the desired sequence. The intermediately resulting N-terminal protected peptide resins are deblocked by means of the reagents described above before linkage with the subse-quent amino acid derivative.
All possible activating reagents used in peptide syn-thesis can be used as coupling reagents, see, for ex-ample, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 15/2, in par-ticular, however, carbodiimides such as, for example, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropyl-carbodi-imide or N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide.
The coupling can in this case be carried out directly by addition of amino acid derivative and the activating reagent and, if desired, a racemization-suppressing additive such as, for example, 1-hydroxy-benzotriazole (HOBt) (W. Ronig, R. Geiger, Chem. Ber. 103, 708 (1970)) or 3-hydroxy-4-oxo-3,4-dihydrobenzo-triazine (HOObt) (W. Ronig, R. Geiger, Chem.Ber. 103, 2054 (1970)) to the resin or, however, the preactivation of the amino acid derivative as symmetrical anhydride or HOBt or HOObt ester can be carried out separately and the solution of 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 with one of the abovementioned activating reagents 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 - 14 - ~ 13~4~6'~
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 Q-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. ~ 595 (1970). The synthesis can also be auto-mated, for example using a peptide synthesizer model 430A
from Applied Biosystems, it being possible either to use the synthesis program provided by the apparatus manufac-turer or else, however, 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 des-cribed manner, the peptide can be split off from the resin using reagents, such as, for example, liquid hydrogen fluoride (preferably in the peptides prepared according to the Boc method) or trifluoroacetic acid (preferably in the peptides synthesized according to the Pzaoc method). These reagents 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 us ing BHA and 1~HA res ins . With the BHA or I~FiA
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 Canadian Patent Applications 563,530 and 586,639. 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 - l3~Ob6'~
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 .
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 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 used.
For the synthesis of peptides having a C-terminal amide grouping or an ~-amino or ~-guanidinoalkyl grouping, the modified support resin described by Sheppard is likewise used. After the synthesis, the peptide fully protected in the side chain is split off from the resin and subse quently reacted with the appropriate amine or ~-amino alkylamine or ~-guanidinoalkylamine in classical solution synthesis, it being possible for optionally present additional functional groups to be temporarily protected in a known manner.
An additional process for the preparation of peptides having an ~u-aminoalkyl grouping is described in Canadian Patent Application 549,680.
The peptides of the present invention were preferably synthesized by two general protective group tactics using the solid phase technique:
The synthesis was carried out using an automatic peptide synthesizer model 430 A from Applied Biosystems, with Boc or Fmoc protective groups for temporary blockage of r.ne 1340b~7 a-amino group.
When using the Boc protective group, the synthesis cycles _ pre-programmed by the manufacturer of the apparatus were 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. 43, 2845 (1978)) from 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 reagents. Activation was carried out as the symmetrical 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 F'moc protective group for the temporary protection of the a-amino group, our own synthesis programs were used for synthesis using the automatic peptide synthesizer model 430A from Applied Biosystems. The synthesis was carried out on a p-ben-zyloxybenzyl alcohol resin (S. Wang, J.Am.Chem.Soc. ~5, 1328 (1973)) from Bachem which was esterified by a known 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 HOBt or HOObt esters was 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 weighed-in mixture of amino acid derivative and HOBt or HOObt. Fmoc-amino acid-OObt esters prepared in substance can likewise be employed as described in EP-A 0 247 573 (published 02 December 1987). The splitting - 17 - ~ :13~0~~7 off of the Fmoc protective group was carried out using a 20% strength solution of piperidine in DMF in the reaction vessel. The excess of reactive amino acid derivative used was 1.5 to 2.5 equivalents. If the coupling was not complete, it was repeated 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 Exp. Pharmacol. Vol. 25, Springer Verlag, 1970, p. 53-55), for example on the isolated rat uterus, on the guinea pig ileum or on the isolated pulmonary artery of the guinea pig.
For testing the peptides according to the invention on 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 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 which is filled with Ringer solution.
Composition of the solution in mmol/1 NaCl 154 RC1 5.6 CaCl2 1. 9 NaHC03 2 . 4 Glucose 5.0 95% OZ and 5% C02 is bubbled through the solution, which is warmed to 37°C. The pH is 7.4 and the preload on the vessel strip is 1.0 g.

.~3~0~67 The isotonic contraction changes are detected using a lever arrangement and an HF modem (position sensor) from Hugo Sachs and recorded on a compensating recorder (BEC, Goerz Metrawatt SE 460).
After equilibration for 1 hour, the experiment is begun.
After the vessel strips have achieved their maximum sensitivity to 2 x 10~' mol/1 of bradykinin - bradykinin leads to a contraction of the vessel strips - the pep-tides are allowed to act for 10 minutes in each case in the doses 5 x 10-e - 1 x 10-5 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 x 10-s - 1 x 10-' mol/1.
The ICso values of the peptides according to the invention calculated from the dose-effect curves are shown in Table 1.
Table 1:
Compound ICso [M]
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH 4,6 10-6 H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Thia-Arg-OH 2,1 10-6 H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH 1,2 10-5 H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Glo-(D)-Tic-Phe-Arg-OH 2,4 10-5 H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-OH2,5 10-5 H-(0)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Pro-Arg-OH 2,5 10-7 H-(D)-Arg-Arg-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 10-8 H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-~-Ala-(D)-Tic-Aoc-Arg-OH1,7 10-6 H-(D)-Arg-Arg-Hyp-Pro-G)y-Thia-Ser-Gly-(D)-Tic-Aoc-Arg-OH3,9 10-~

H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-(D)-Tic-(D,L)-Oic-Arg-OH3,2 10-7 H-(D)-Arg-(D)-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH4,8 10-~

H-(D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-(D)-Tic-Tir-Arg-OH 1,7 10-7 1340b6°~

Compound ICso [M]
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 1,1 ~

H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH 4,6 -H-(D)-Tyr-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Aoc-Arg-OH 6,2 10-8 H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-(D)-Dic-Arg-OH2,6 -H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH 5,4 -H-(D)-Arg-Lys-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Aoc-Arg-OH 3,2 10-~

H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH 6,8 -H-(D)-Arg-Arg-(N02)-Pro-Hyp-Gly-Phe-Ser-(0)-Tic-Aoc-Arg-OH6,4 10-8 H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH 4,2 -H-(D)-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH 3,4 10-~

H-Arg-(Tos)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Dic-Arg-OH 3,0 10-8 H-Arg-(Tos)-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Dic-Arg-OH 1,8 -The therapeutic utility of the peptides according to the invention includes all pathological states which are mediated, caused or supported by bradykinin and brady-kinin-related peptides. This includes, inter alia, traumas, such as wounds, burns, rashes, erythemas, edemas, angina, arthritis, asthma, allergies, rh initis, 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 pharma-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.
Administration 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 mammal species, the body weight, age and on the manner of administration.

20 - 13~0~67 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 excipients, stabilizers or inert diluents, and brought into suitable forms for admini-stration, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, 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 moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil and cod liver oil.
A preparation for topical application may be present as an aqueous 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 suit-able forms for administration, such as aqueous, alcohol-ic or oily suspensions or aqueous, alcoholic or oily solutions, by customary methods. Chelating agents, ethylenediamine-N,N,N',N'-tetraacetic acid, citric acid, tartaric acid or their salts may be added to aqueous 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.

~3~0~~7 For administration by inhalation, atomizers or pressurized gas packs using inert carrier gases can be used.
For intravenous, subcutaneous, epicutaneous or intra-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, 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 may be used are, for example, oily crystal suspensions, microcapsules, rods or implants, it being possible to synthesize the latter from tissue-compatible polymers, in particular biodegradable polymers, such as, for example, those based on polylactic acid/ polyglycolic acid copolymers or human albumin.
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:
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 E-AhX E-Aminohexanoyl Aoc cis, endo-2-Azabicyclo[3.3.0]octane-3-S-carbonyl Boc tert-Butyloxycarbonyl But tert-Butyl Bzl Benzyl C1-Z 4-Chlorobenzyloxycarbonyl DME 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 2.2,5,7,8-Pentamethylchroman-6-sulfonyl TFA Trifluoroacetic acid Tcs 4-Methylphenylsulfonyl Thia 2-Thienylalanyl Tic 1,2,3,4-Tetrahydroisoquinolin-3-ylcarbonyl Trt Trityl The following examples are intended to illustrate the preferred methods for solid phase synthesis of the peptides according to the invention, without limiting the invention thereto.
The amino acid derivatives below were used:
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-S-Ala-OH, Fmoc-Oic-OH.
Example l:
H-(D)-Arg-Arg-Hyp-pro-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH
was synthesized stepwise using a peptide synthesizer model 430 A from Applied Biosystems by the Fmoc method on a p-benzyloxybenzyl alcohol resin from (loading about 0.5 mmol/g of zesin) esterified with Finoc-Arg(Mtr)-OH. 1 g of the resin was employed and the synthesis was carried out with the aid of a synthesis program modified for the Fmoc method.
In each case 1 mmol of the amino acid derivative having a free carboxyl group together with 0.95 mmol of HOObt 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.
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 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 residue which 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) : 1294 (M+H) 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) Example 4:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D)-Tic-Phe-Arg-OH
MS(FAB) . 1294 (M+H) Example 5:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Phe-Gln- (D)-Tic-Phe-Arg-OH
MS(FAB) . 1335 (M+H) Example 6:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D)-Tic-Pro-Arg-OH
MS(FAB) . 1244 (M+H) Example 7:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Phe-Trp- (D)-Tic-Phe-Arg-OH
MS(FAE) . 1393 (M+H) Bzample 8:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Pro-Arg-OH
MS(FAB) . 1250 (M+H) Example 9:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia- (D)-Asn- (D)-Tic-Thia-Arg-OH
MS(FAB) . 1333 (M+H) Baample 10:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Opr- (D)-Tic-Thia-Arg-OH
MS(FAB) . 1301 (M+H) Example 11:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia- (D)-Gln- (D)-Tic-Thia-Arg-OH
MS(FAB) . 1347 (M+H) Example 12:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D)-Tic-Pro-Arg-OH
MS{FAB) . 1307 (M+H) Example 13:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Pro-Phe-OH
MS(FAB) . 1241 (M+H) _ 25 - 134~~67 Example 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) Example 16:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D)-Tic-Pro-Arg-OH
MS(FAB) . 1220 (M+H) Example 17:
H- (D)-Arg-Arg-Aoc-Pro-Gly-Thia-Ser- (D}-Tic-Thia-Arg-OH
MS(FAB) . 1330 (M+H) Example 18:
H- (D)-Arg-Arg-pro-Aoc-Gly-Thia-Ser- (D)-Tic-Thia-Arg-OH
MS(FAB) . 1330 (M+H) Example 19:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D}-Tic-Aoc-Arg-OH
MS(FAB) . 1290 (M+H) Example 20:
H- (D)-Arg-Arg-Opr-Pro-Gly-Thia-Ser- (D)-Tic-Pro-Arg-OH
MS(FAB) . 1236 (M+H) Example 21:
H- (D)-Arg-Arg-Pro-Opr-Gly-Thia-Ser- (D)-Tic-Pro-Arg-OH
MS(FAB} . 1236 (M+H) Eaample 22:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Opr-Arg-OH
MS(FAB) . 1252 (M+H) Example 23:
H- (D)-Arg- (D)-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1290 (M+H) - 26 - 134p~~~
Example 24:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1290 (M+H) Eaamples 25 - 27:
H-(D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg-OH
and H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-OH
and H-(D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Phe-Arg(Mtr)-OH
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 minutes at room temperature. Under the conditions 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. H- (D)-Arg-Arg(Mtr)-Pro-Hyp-Gly-Phe-Ser- (D)-Tic-Phe-2 0 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) 2~= 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) ~340~b7 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) Ezample 32:
H-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Phe-NH-(CH2)4-NH2.
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=C
Fmoc- NH- ( CH2 ) 4- NH- CO- O- CH2- ; ~C- 0- CH2- CO-C- C
described in EP-A 264,802, using Fmoc-amino acid-OObt esters with an automatic peptide synthesizer (model 430A
from Applied Biosystems) and synthesis programs which have themselves been modified. To this end, in each case 1 mmol of the appropriate amino acid derivative was weighed into the cartridges provided by the manufacturer, and Fmoc-Arg(Mtr)-OH, Fmoc-Hyp-OH and Fmoc-(D)-Tic-OH
were weighed into the cartridges together with 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 were 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-.~340b67 - 2g _ 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 32:
Ezample 33:
H-D-Arg-Arg-Hyp-Pro-Gly-Phe-Ser- (D)-Tic-Phe-NH- (CH2)4-NH2 MS(FAB): 1208 (M+H) Ezample 34:
HOOC- (CH2 )2-CO-Arg-Hyp-Pro-Gly-Phe-Ser- (D)-Tic-Phe-NH-( CH2 ) 4- ~2 MS(FAB): 1152 (M+H) Ezample 35:
HOOC- (CH2)2-CO- (D)-Arg-Hyp-Pro-Gly-Phe-Ser- (D)-Tic-Phe-NH-( CH2 ) 4- NH2 MS ( FAB ) : 13 0 8 ( M+H ) The examples 36 to 161 were synthesized according to the method described under Example 1.
Ezample 36:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-Gly- (D)-Tic-Pro-Arg-OH
MS(FAB} . 1307 (M+H) Ezample 37:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-Gly- (D)-Tic-Pro-Arg-OH
MS(FAB) . 1307 (M+H) Ezample 38:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Pro-Phe-OH
MS(FAB) . 1241 (M+H) A

Ezample 39:
H- (D)-Arg-Arg-Hyp-pro-Gly-Thia-Ser-S-Al a- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1361 (M+H) Example 40:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-p-Ala- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1361 (M+H) Example 41:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Pro-Phe-Arg-OH
MS(FAB) . 1397 (M+H) Example 42:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser- ~D)-Tic-Pro-Phe-Arg-OH
MS(FAH) . 1397 (M+H) Example 43:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Gly- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1260 (M+H) Ezample 44:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia-Gly- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1260 (M+H) Example 45:
H- (D)-Arg- (D)-Arg-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1290 (M+H) Example 46:
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) Example 48:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Tic-Arg-OH
MS(FAB) . 1312 (M+H) 1340~6'~
Example 49:
H- {D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1274 (M+H) Example 50:
H- (D)-Arg-Arg-Hyp-Pro-Gly-Thia- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1203 (M+H) Example 51:
H- (D)-Arg-Arg-Hyp-pro-Gly-Aoc-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1274 (M+H) Example 52:
H- (D)-Arg-Arg-Hyp-pro-Gly-Thia-d-Ala- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1274 (M+H) Example 53:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-p-Al a- (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) Example 56:
H- (D)-Arg-Arg-Hyp-pro-Gly-Trp-Ser- (D)-Tic-Aoc-Arg-OH
MS{FAB) . 1323,7 (M+H) Example 57:
H- (D)-Tyr-Arg-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1297,7 (M+H) Example 58:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser- (D)-Tic- (D)-Oic-Arg-OH
MS(FAB) . 1304,6 (M+H) - 31 - 1~40~67 Example 59:
H- (D)-Arg-Arg-pro-Hyp-Gly-Thia-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1304,6 (M+H) Example 60:
H- (D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1289 (M+H) Example 61:
H- (D)-Arg-Lys-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAH) . 1262 (M+H) Example 62:
H- (D)-Arg-Lys-Pro-Hyp-Gly-This-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1276 (M+H) Example 63:
H- (D)-Arg-Lys-Pro-Pro-Gly-Thia-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1260 (M+H) Example 64:
H- (D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1298 (M+H) Example 65:
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH
MS(FAB) . 1298 (M+H) Example 66:
H- (D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1282 (M+H) Example 67:
H-(D)-Arg-Arg(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 - ~~~~~~7 Ezample 69:
H- (D)-Arg-Arg(N02)-Pro-Pro-Gly-Phe-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1327 (M+H) Ezample 70:
H- (D)-Arg-Arg(N02)-Pro-Pro-Gly-Thia-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-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1302 (M+H) Ezample 73:
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 ( Nicot inoyl ) - 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- T1 c- Aoc- Arg- OH
MS(FAB) . 1282 (M+H) .~340b67 Ezample 78:
Ac- Arg ( Tos ) - Pro- Hyp- Gly- Phe- Ser- D- Tic- Aoc- Arg- OH
MS(FAB) . 1324 (M+H) Eaample 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- G1 y- Phe- S er- D- Ti c- Oi c- Arg- OH
MS(FAB) . 1142 (M+H) Ezample 82:
H-Lys (-CO-NH-C6H5)-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) Example 84:
H-Lys (Nicotinoyl )-Hyp-Pro-Gly-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) Example 86:
Ac-Arg(Tos)-Hyp-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH
MS(FAB) . 1324 (M+H) Ezample 87:
H-D-Arg-Arg (Tos ) -Hyp-Pro-Gly-Phe- Ser-D-Tic-Aoc-Arg- OH
MS(FAB) . 1438 (M+H) - 34 - 13~0~~~
Example 88:
H- Arg ( Tos ) - Pro- Pro- Gly- Thi a- Ser- D- Ti c- Oi c- 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- Ly s ( - CO- NH- C6H5 ) - Pro- Pro- G1 y- Phe- Ser- D- Ti c- Oi c- Arg- OH
MS(FAB) . 1217 (M+H) Example 91:
H-Arg ( Tos ) - Pro- Pro- Gly- Phe- Ser- D- Tic- Oic- Arg- OH
MS(FAB) . 1280 (M+H) Ezample 92:
H- Lys ( Nicot inoyl ) - Pro- Pro- G1 y- Phe- Ser- D- Tic- Oic- Arg- OH
MS(FAB) . 1203 (M+H) Example 93:
H- Arg ( Tos ) - Pro- Pro- G1 y- Phe- Ser- D- Tic- Aoc- Arg- OH
MS(FAB) . 1266 (M+H) Ezample 94:
Ac-Arg(Tos)-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH
MS(FAB) . 1308 {M+H) Example 95:
H-D-Arg-Arg ( Tos ) -Pro- Pro- Gly-Phe- Ser-D-Tic-Aoc-Arg-OH
MS(FAB) . 1422 (M+H) Example 96:
H-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1148 (M+H) Example 97:
H-Lys (-CO-NH-C6H5 )-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1239 (M+H) ~~~Obh7 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- Th i a- Ser- D- Tic- Aoc- Arg- OH
MS(FAB) . 1330 (M+H) Example 101:
H- D- Arg- Arg ( Tos ) - Pro- Hyp- Gly- Thi a- Ser-D- Tic- Aoc-Arg- OH
MS(FAB) . 1444 (M+H) Ezample I02:
H- Arg- Hyp- Pro- Gly- Thi a- Ser- D- Tic- Oic- Arg- OH
MS(FAB) . 1I48 (M+H) Example 103:
H-Lys (-CO-NH-C6H5 )-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) Example 105:
H-Arg(Tos)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH
MS(FAB) . 1288 (M+H) Example 106:
Ac- Arg ( Tos ) - Hyp- Pro- G1 y- Thi a- Ser- D- Ti c- Aoc-Arg- OH
MS(FAB) . 1330 (M+H) Ezample 107:
H- D- Arg- Arg ( Tos ) - Hyp- Pro- Gly- Th i a- S er- D- Ti c- Aoc- Arg- OH
MS(FAB) . 1440 (M+H) 1344b67 Example 108:
H- Lys ( - CO- NH- C6H5 ) - Pro- Pro- Gly- Thi a- Ser- D- Tic- Oi c- Arg- OH
MS(FAB) . 1225 (M+H) Example 109:
H- Lys ( Nicotinoyl ) - Pro- Pro- Gly- Thia- Ser-D- Tic- Oic-Arg- OH
MS(FAB) . 1209 (M+H) Example 110:
H-Arg (Tos )-Pro-Pro-Gly-Thia-Ser-D-Tic-Aoc-Arg-OH
MS(FAB): 1272 (M+H) Example 111:
Ac- Arg ( Tos ) - Pro- Pro- Gly-Thia- Ser-D-Tic-Aoc-Arg- OH
MS(FAB) . 1314 (M+H) Example 112:
H-D-Arg-Arg ( Tos )-Pro-Pro- Gly-Thia- Ser-D-Tic-Aoc-Arg- OH
MS(FAB) . 1428 (M+H) Example 113:
H-D-Arg-Lys (Nicotinoyl )-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg- OH
MS{FAB) . 1365 (M+H) Ezample 114:
H-D-Arg- Lys (- CO-NH- C6H5 ) -pro-Pro- Gly-Thia- Ser-D-Tic-Oic-Arg- OH
MS{FAB) . 1379 (M+H) Example 115:
H-D-Arg-Arg(Tos )-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1442 (M+H) Example 116:
H-Lys-Lys- (Nicotinoyl)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1337 (M+H) Example 117:
H- Lys- Lys ( - CO- NH- C6H5 ) - Pro- Pro- G1 y- Th i a- S er- D- Ti c- 0 i c-Arg-OH
MS(FAB) . 1351 (M+H) Example 118:
H-Lys-Arg(Tos)-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1414 (M+H) Example 119:
H-D-Arg-Lys (Nicotinoyl )-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1381 (M+H) Example 120:
H-D-Arg-Lys- (CO-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg- OH
MS(FAB) . 1395 (M+H) Example 121:
H- D- Arg- Arg ( Tos ) - Pro- Hyp- G1 y- Thi a- Ser- D- Ti c- Oi c- Arg- OH
MS(FAB) . 1458 (M+H) Example 122:
H- Lys- Lys ( - CO- NH- C6H5 ) - Pro-Hyp- Gly- Thi a- Ser-D- Tic- Oic-Arg- OH
MS(FAB) . 1367 (M+H) Example 123:
H- Lys- Lys ( Nicotinoyl ) - Pro-Hyp- Gly- Thia- Ser-D- Tic- Oic-Arg-OH
MS(FAB) . 1353 (M+H) Example 124:
H- Lys- Arg ( Tos ) - Pro- Hyp- G1 y- Th i a- Ser- D- Tic- Oic- Arg- OH
MS(FAB) . 1430 (M+H) - 38 - 134Ub67 Example 125:
H-D-Arg-Lys (Nicotinoyl )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1359 (M+H) Ezample 126:
H- D- Arg- Lys ( - CO- NH- C6H5 ) - Pro- Pro- Gl y- 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 (Nicotinoyl )-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1331 (M+H) Ezample 129:
H- Lys- Lys ( - 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 (Nicotinoyl ) -Pro-Hyp-Gly-Phe- Ser-D-Tic- Oic-Arg-OH
MS(FAB) . 1375 (M+H) Example 132:
H- D- Arg- Lys ( - CO- NH- C6H5 ) - Pro- Hyp- Gly- Phe- S er- D- Tic- Oi c-Arg-OH
MS(FAB) . 1389 (M+H) Example 133:
H- D- Arg- Arg ( Tos ) - Pro- Hyp- Gly- Phe- S er- D- Ti c- Oic- Arg- OH
MS(FAB) . 1452 (M+H) Example 134:
H- Lys- Lys ( Nicot inoyl ) - Pro- Hyp- Gly- Phe- Ser- D- Tic- Oic- Arg- OH
MS(FAB) . 1347 ,(M+H) Eaample 135:
H- Lys- Lys ( - CO- NH- C6H5 ) - Pr o- Hyp- G1 y- Phe- Ser- D- Ti c- Oi c- Arg-OH
MS(FAB) . 1361 (M+H) Example 136:
H-Lys-Arg (Tos )-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1424 (M+H) Example 137:
H-D-Arg- Orn ( Nicotinoyl ) - Pro- Pro- Gly- Thia- Ser-D-Tic- Oic-Arg-OH
MS(FAB) . 1351 (M+H) Example 138:
H- D- Arg- Orn ( - CO- NH- C6H5 ) - Pro- Pro- G1 y- Thi a- Ser-D- Tic- Oic-Arg- OH
MS(FAB) . 1428 (M+H) Eaample 139:
H-Lys-Orn (Nicotinoyl )-Pro-Pro-Gly-Thia-Ser-D-Tic-Oic-Arg-oH
MS(FAB) . 1323 (M+H) Example 140:
H- Lys- Orn ( - CO- NH- C6H5 ) - Pro- Pro- Gly- Thi a- Ser- D- Ti c- Oi c- Arg-OH
MS(FAB) . 1337 (M+H) Example 141:
H-D-Arg-Orn(Nicotinoyl)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1367 (M+H) 1340b67 Example 142:
H-D-Arg-Orn(-CO-NH-C6H5)-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg- OH
MS(FAB) . 1381 (M+H) Example 143:
H-Lys-Orn(Nicotinoyl ) -Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1339 (M+H) Example 144:
H- Lys- Orn ( - CO-NH- C6H5 ) -Pro-Hyp- Gly-Thia- Ser-D-Tic- Oic-Arg-OH
MS(FAB) . 1353 (M+H) Example 145:
H-D-Arg-Orn(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1345 (M+H) Example 146:
H-D- Arg- Orn ( - CO-NH- C6H5 ) - Pro-Pro- Gly- Phe- Ser-D-Tic- Oic- Arg-oH
MS(FAB) . 1359 (M+H) Example 147:
H-Lys-Orn(Nicotinoyl)-Pro-Pro-Gly-Phe-Ser-D-Tic-Oic-Arg-OH
MS(FAB) . 1317 (M+H) Example 148:
H- Lys- Orn ( - CO- NH- C6H5 ) - 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) 134Qb67 Example 150:
H-D-Arg-Orn(CO-NH-C6H5)-Pro-Hyp-Gly-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- C6H5 ) - Pro- Hyp- Gly- Phe- Ser- D- Ti c- O i c- 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) Ezample 154:
H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1234 (M+H) Ezample 155:
H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D}-Tic-Aoc-Arg-OH
MS(FAB) . 1234 (M+H) Ezample 156:
H-Lys-Lys-Pro-Pro-Gly-Phe-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1212 (M+H) Example 157:
H-Lys-Lys-Pro-Hyp-Gly-Phe-Ser- (D)-Tic-Aoc-Arg-OH
MS(FAB) . 1228 (M+H) Example 158:
H-Lys-Lys-Pro-Pro-Gly-This-Ser- (D}-Tic-Oic-Arg-OH
MS(FAB} . 1232 (M+H) _ 42 _ 1 Example 159:
H-Lys-Lys-Pro-Hyp-Gly-Thia-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1248 (M+H) Example 160:
H-Lys-Lys-Hyp-Pro-Gly-Thia-Ser- (D)-Tic-Oic-Arg-OH
MS(FAB) . 1226 (M+H) Ezample 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 32 using the resin having the structure Fr.,oc-NH OCH3 i OCH3 CH2 ~CH3 I
CHp I
C' 0 I
NH
I

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) _ 43 _ Example 164:
H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-NH2 MS(FAB): 1267 (M+H) SUPPLEMENTARY DISCLOSURE
The compounds of Examples 165-194 were prepared analogously to Example 1:
Example 165 H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-0H
MS(FAB): i 267 (M + H) Example 166 H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-0H
MS(FAB): 1284 (M+H) Example 167 H-D-Arg-Lys(~-Pro-Hyp-Gly-Phe-Ser-D;~Tic-Aoc-Arg-OH
MS(FAB): 1390.7 (M+H) Example 168 H-D-Arg-Lys-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-0H
MS(FAB): 1256.7 (M+H) Example 169 H-D-Arg-Ser(Rha)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-0H
MS(FAB): 1361 (M+H) Example 170 H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-D-Ser(Rha)-OH
MS(FAB): 1345 (M + H) Example 171 H-D-Arg-Arg(Tos)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg(Mtr)-OH
MS(FAB): 1650.7 (M+H) ~5 ' l~~~b~~
Example 172 H-D-Arg-Arg-Hyp-Pro-Gly-Thia-Ser-D-Tic-D-Aoc-Arg-OH
MS(FAB): 1290 (M + H) Example 173 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-D-Oic-Arg-OH
MS(FAB): 1304.7 (M+H) Example 174 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1302.7 (M + H) Example 175 H-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-4ic-Arg-0H
MS(FAB): 1304.7 (M + H) Example 176 4-Hydroxyphenylpropionyl-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-0H
MS(FAB): 1452.7 (M+H) Example 177 H-D-Arg-D-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1304.7 (M + H) Example 178 H-D-Arg-Arg-D-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1304.6 (M + H) Example 179 - H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-D-Arg-OH
MS(FAB): 1304.9 (M + H) D

Example t 80 H-D-Arg-Arg-Pro-Hyp-Gly-D-lhia-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1304.8 (M + H) Example 181 H-D-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1148 (M + H) Example 182 H-D-Arg-Arg-Pro-Hyp-Gly-lhia-Ser-D-Tic-Oic-0H
MS(FAB): 1147 (M + H) Example 183 H-D-Arg-Arg-Pro-Hyp-Gty-Thia-D-Ser-DtTic-0ic-Arg-OH
MS(FAB): 1304.7 (M + H) Example 184 Ac-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FA8): 1346.9 (M+H) Example 185 H-D-Arg-Arg (Mtr)-Hyp-Pro-Gly-Thia-Ser-D-Tic-Pro-Phe-OH
MS(FAB): 1454.9 (M+H) Example 186 H-D-Arg-Arg-Hyp-Pro-Gly-Thia-Gly-D-Tic-D, L-Oic-Arg-OH
MS(FAB): 1274 (M+H) Example 187 H-D-Arg-Arg-Hyp-Pro-Gly-lhia-B-Ala-D-Tic-Aoc-Arg-OH
MS(FAB): 1354.6 (M + H) _ ~' - ~~40067 ~,r,~s ,es H-D-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1142.5 (M+H) Example 189 (4-Benzoyl)phenoxyacetyl-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1542.6 (M+H) Example 190 H-((4-Benzoynbenzyol}-Lys-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH
MS(FAB): 1640.9 (M+H) Example 191 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Gys-D-Tic-Oic-Arg-OH
MS(FAB}: 1320.7 (M+H) Example 192 H-D-Arg-Arg-Pro-Hyp-Gty-Thia-Ser-D-Tic-(3aR,7aS)Oic-Arg-OH
MS(FAB): 1304.7 (M+H) Example 193 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-(3aS,7aR)Oic-Arg-OH
MS(FAB): 1304.7 (M+H) Example 194 H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-NH2 MS(FAB): 1147.6 (M+H) ICS-data for the compounds of Examples 1 to 194 is provided in Table I.

- .~340~~7 Example 195 H-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-OH
The peptide of Example 195 was prepared analogously to Example 1, however, the peptide was split off from the resin as follows:
The peptide resin is treated with a mixture of m-cresols and dichloromethane (1:2) (about 2ml/g resin) for 10 min to swell the resin. Then trifluoroacetic acid (about 10 ml/g resin) and with stirring bromotrimethylsilane (about 0.8 ml/g resin) is added.
After 1.5 h reaction time the mixture is filtered through a sintered glass funnel into icecold methyl-tert.butylether. The precipitated aude peptide is collected by filtration, washed with methyl-tert.butylether and then dried. The aude peptide is dissolved in water) the aqueous solution is extracted with ethylacetate and then treated with ion exchange resin (IRA 93, acetate form). The ion exchanger is removed by filtration) washed with water and the aqueous solution is lyophilized. The crude peptide now obtained as acetate is purfied by chromatography on mSephadex LH 20 with 10 %
aqueous acetic acid. The fractions which contain the pure peptide are combined and lyophilized.
MS (FAB) : 992.6 (M + H).

TABLEI ~.34U~67 Example No. ICSO[M]
1 4.6 x 10-6 3 2.1 x 10-6 4 1.2 x 10-5 2.4 x 10-5 6 2.5 x 10-~

7 3.7 x 10-5 8 1.9 x 10-~

9 4.6 x 10-5 13 6.0 x 10-5 19 3.4 x 10-8 23 4.8 x 10-~

24 1.1 x 10-8 27 2.5 x 10-5 29 3.7 x 10-~

38 6.0 x 10-5 39 1.7 x 10-6 44 3.9 x 10-~

45 4.8 x 10-~

47 1.7 x 10-~

48 9.5 x 10-8 54 8.9 x 10-6 56 8.0 x 10-~

57 6.2 x 10-8 58 2.6 x 10-5 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 10-8 73 3.0 x 10-8 74 4.8 x 10-8 75 3.0 x 10-8 76 3.2 x 10-~

77 7.0 x 10-8 78 2.5 x 10-~

79 3.5 x 10-8 r TABLE 1 cont'd Example No. ICSO[M]
159 7.8 x 10-8 162 7.2 x 10-~

165 3.0 x 10-8 166 4.6 x 10-8 167 2.8 x 10-~

168 3.2 x 10-~

169 2.0 x 10-~

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-~

178 1.3 x 10-~

179 1.8 x 10-~

180 1.8 x 10-~

181 2.4 x 10-~

182 2.9 x 10-~

183 8.0 x 10-6 184 2.3 x 10-8 185 4.4 x 10-6 186 3.2 x 10-~

188 3.4 x 10-~

189 1.6 x 10-8 190 6.6 x 10-9 191 1.2 x 10-8 192 1.5 x 10-~

193 8.9 x 10-8 194 4.2 x 10-8

Claims

1. A peptide of the formula I

A-B-C-E-F-K-(D)-Tic-G-M-F'-I (I), in which A a1) denotes hydrogen, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl or (C1-C8)-alkylsulfonyl in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or 3 identical or different radicals from the series comprising carboxyl, amino, (C1-C4)-alkyl, (C1-C4)-alkylamino, hydroxyl, (C1-C4)-alkoxy, halogen, di-(Cl-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C12)-aryl and (C6-C12)-aryl-(C1-C5)-alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical from the series comprising (C3-C8)-cycloalkyl (C1-C4)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (C6-C12)-aryl-(Cl-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylsulfinyl, (C6-C12)-aryloxy, (C3-C9)-heteroaryl and (C c -C9)-heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals from the series comprising carboxyl, ammo, (C1-C4)-alkylamino, hydroxyl, (C1-C4)-alkoxy, halogen, di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C12)-aryl and (C6-C12)-aryl-(C1-C5)-alkyl, a2) denotes (C3-C8)-cycloalkyl, carbamoyl, which may be optionally substituted on the nitrogen by (C1-C6)-alkyl or (C6-C12)-aryl, (C6-C12)-aryl, (C7-C18)-aryloyl, (C5-C12)-arylsulfonyl (C3-C9)-heteroaryl or (C3-C9)-heteroaryloyl, where in the radicals defined under a1) and a2) in each case heteroaryl, 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, (Cl-C4)-alkoxy, halogen, cyano, di-(C1-C4)-alklamino, carbamoyl, sulfamoyl and (C1-C4)-alkoxycarbonyl, or a3) denotes a radical of the formula II

(II) where R1 is defined as A under a1) or a2), R2 denotes hydrogen or methyl, R3 denotes hydrogen or (C1-C4)-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, 4-hydroxyphenyl, phthalimido, 4-imidazolyl 3-indolyl,

2-thienyl

3-thienyl, 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 a1) or a2);
B is Arg, Lys, Orn, 2, 4-diaminobutyroyl or an L-homoarginine radical, where in each case the amino or the guanidino group of the side chain can be substituted by A as described under a1) or a2);
C stands for a compound of the formula IIIa or IIIb G'-G'-Gly ~~G'-NH-(CH2)n-CO
(IIIa) ~~ (IIIb) in which G' independently of one another are a radical of the formula IV

, in which R(4) and R(5) together with the atoms carrying them from a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms, and n is 2 to 8;
E is the radical of phenylalanine, which is optionally substituted by halogen in the 2-, 3- or

4-position, tyrosine, 0-methyltyrosine, 2-thienylalanine, 2-pyridylalanine or naphthylalanine;
F independently of one another denotes the radical of a neutral, acidic or basic, 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 the radical of the basic amino acids Arg or Lys, in the L- or D- form, or a direct bond, where the guanidino group or amino group of the side chain can be substituted by A as described under a1) or a2), or a radical -NH-(CH2)n- with n = 2 - 8;
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.

2. A peptide as claimed in claim 1, wherein the formula II

R1 and R2 are as claimed in claim 1 R3 denotes ((C1-C4)-alkyl which is optionally monosubstituted by amino.

3. A peptide of the formula I as claimed in claim 1 in which B denotes Arg, Orn or Lys, where the guanidino group or the amino group of the side chain is unsubstituted or may be substituted by (C1-C8)-alkanoyl, (C7-C13)-aryloyl, (C3-C9)-heteroaryloyl, (C1-C8)-alkylsulfonyl or (C6-C12)-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 .beta.-(2-thienyl) alanine;
K stands for a direct bond and M stands for a direct bond.

4. A peptide for the formula I as claimed in claim 2 in which A denotes hydrogen, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or (D)- or (L)-H-Orn;
B denotes Arg, Orn or Lys, where the guanidino group or the amino group of the side chain is unsubstituted or may be substituted by (C1-C8)-alkanoyl, (C7-C13)-aryloyl, (C3-C9)-heteroaryloyl, (C1-C8)-alkylsulfonyl or (C6-C12)-arylsulfonyl where the aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl radicals may optionally be substituted with 1, 2, 3 or 4 identical or different radicals from the group comprising methyl, methoxy and 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;
K stands for a direct bond and M stands for a direct bond;
G stand for a heterocylic ring system of the formula IV, selected from the radicals of the heterocycles pyrrolidine (A); piperidine (B); tetrahydroisoquinoline (C); cis- and trans-decahydroisoquinoline (D); cis-endo-octahydroindole (E), cis-exo-octahydroindole (E), trans-octahydroindole (E), cis-endo-, cix-exo-, trans-octahydrocyclopentano[b]pyrrole, (F) or hydroxyproline (V) F' is Arg I is OH

5. A peptide of the formula I as claimed in claim 1, which is selected from the group comprising:
H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH, H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.

6. A process for the preparation of a peptide of the formula I as claimed in any one of claims 1 to 4, which comprises a) reacting a fragment having a C-terminal free carboxyl 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 temporarily 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 physiologically tolerable salts.

7. Use of a peptide of the formula I as claimed in any one of claims 1 to 4 for the treatment of pathological states which are mediated, paused or supported by bradykinin and bradykinin-related peptides.

8. A pharmaceutical agent containing a peptide of the formula I as claimed in any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

9. A peptide of the formula I as claimed in any of claims 1 to 4 for use in the treatment of pathological states which are mediated, caused or supported by bradykinin and bradykinin-related peptides.

10. A peptide of the formula H-(D)-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-(D)-Tic-Oic-Arg-OH, wherein Thia denotes 2-thienyalanyl, (D)-Tic denotes the radical of the formula V

and Oic denotes is-endo-octahydroindol-2-ylcarbonyl.

11. A peptide of the formula H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH
wherein D-Tic is a radical of the formula V

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

12. A peptide of the formula H-D-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH, wherein D-Tic and Aoc are as claimed in claim 11.

13. A peptide of the formula H-D-Arg-Lys(Z)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH, wherein D-Tic and Aoc are as claimed in claim 11.

14. A peptide of the formula H-D-Arg-Lys-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH, wherein D-Tic and Aoc are as claimed in claim 11.

15. A peptide of the formula H-D-Arg-Ser(Rha)-Pro-Hyp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OH, wherein D-Tic and Aoc are as claimed in claim 11.

16. A peptide of the formula H-D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-D-Tic-Aoc-D-Ser(Rha)-OH, wherein D-Tic and Aoc are as claimed in claim 11.