BRADYKININ ANTAGONIST PEPTIDES

Abstract: The substitution of the L-Pro at the 7-position of the peptide hormone bradykinin or other substituted analogs of bradykinin with an aliphatic, cyclic or aromatic amino acid of the D-configuration converts bradykinin agonists into a bradykinin antagonist. The invention further includes additional modifications at other positions within the novel 7-position modified bradykinin antagonists including replacement of arginine in the one and nine positions and sequence deletions analogs and C-terminal and N-terminal extensions, which increase enzyme resistance, antagonist potency and/or specificity of the new bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of the mammal and human body in which an excess of bradykinin or related kinins are produced or injected as by bites into the body.

Description: BRADYKININ ANTAGONIST PEPTIDES 1. Cross Reference To Related Applications This invention pertains to new and useful bradykinin antagonist peptides and is related to the subject matter of U.S. Application Serial No. OQI .ggq filed concurrently herewit . 2. Field Of The Invention The invention relates to novel biologically active peptides which act as antagonists of the biological activities of bradykinin, their pharmaceutically acceptable salts, and their application as therapeutic agents. More particularly the invention pertains to bradykinin antagonists having a critical 7 position substitution and lacking an alpha amino group or having a beta amino acid residue alone or together with sequence deletions and with or without an aromatic amino acid residue at position nine. 3. Description Of The Prior Art In the 25 years since the sequence of the potent mammalian vasodilator peptide bradykinin was described and synthesized (Boissonnas et al., Experientia 16:326, 1960) several hundred sequence-related peptide analogs have been synthesized and assayed in biological systems (Schroeder, in Handbook of Experimental Pharmacology, Vol. 25, (Springer Verlag) pp. 324-350, 1970) (Stewart, Handbook of Experimental Pharmacology, Vol. 25 (Supplement) , (Springer Verlag pp.227-272, 1979). The objective in these studies was to investigate the varied physiological and pharmacological roles of bradykinin. Bradykinin, and its physiologically important related peptides kallidin (Lys-bradykinin) and Met-Lys-bradykinin, exhibit physiological actions which qualify them as mediators of inflammatory reactions, hypotensive states, and pain. Bradykinin is overproduced in pathological conditions such as septic shock (Robinson et al.. Am. J. Med. 59.:61, 1975) and hemorrhagic (Hirsch et al., J. Surg. Res. 27:147, 1974) anaphylaxis (Collier and James, J. Physiol. 160:15P. 1966), arthritis (Jasani et al., Am. Rheum. Dis. £8_:497, 1969; Hamberg et al., Agents Actions _§.:50, 1978; Sharma et al., Arch. Int. Phar acodyn. 262:279. 1983), rhinitis (Proud et al., J. Clin. Invest. 22.S 678, 1983; Naclerio et al., Clin. Res. 3_3_:613A, 1985), asthma (Christiansen et al., J. Clin. Invest. 7_9_:188 - 197, 1987) , inflammatory bowel disease (Zeitlin and Smith, Gut 4.:133 - 138, 1973), and certain other conditions including acute pancreatitis, post-gastrectomy dumping syndrome, carcinoid syndrome, migraine, and angioneurotic edema (Leme, Handb. Exp. Pharmacol. 50/1:464 - 522, 1978). The production of bradykinin from the plasma results in pain at the site of the pathological condition, and the overproduction intensifies the pain directly or via stimulation by bradykinin of the activation of the arachidonic acid pathway which produces prostaglandins and leukotrienes, the more distal and actual mediators of inflammation. Literature references describing these actions of bradykinin and related peptides are found in Handbook of Experimental Pharmacology, Vol. 25, Springer-Verlag, 1970 and Vol. 25 Supplement, 1979. Bradykinin as discussed has been found to be produced in inflammatory reactions in the intestine provoking contraction of smooth muscle and secretion of fluid and ions. The existence of specific bradykinin receptors in the mucosal lining of the intestine and intestinal smooth muscle is demonstrated by Manning, et al in Nature (229:256-259, 1982) showing the influence of bradykinin in very low concentrations upon fluid and ion secretion. The production of bradykinin and associated pain in angina has been studied and reported by Kimura, et al in American Heart Journal (85:635-647, 1973) and by Staszewska - Barczak, et al in Cardiovascular Research (10:314-327, 1976). The reported action of bradykinin and prostaglandins acting in concert are the natural stimulus for excitation of the sensory receptors signalling the pain of myocardial ischemia. Bradykinin and bradykinin - related kinins are not only produced by the animal but may also be injected as a result of stings and bites. It is known that insects such as hornets and wasps inject bradykinin related peptides which also cause pain, swelling and inflammation. The search for understanding of the mechanism of action of bradykinin, which is essential for the development of useful tools for diagnostic use, and for the development of therapeutic agents aimed at alleviating the intense pain caused by the production and overproduction of bradykinin, has been severely hindered by the lack of specific sequence-related competitive antagonists of bradykinin. Several non-peptide, non-specific and non-selective antagonists of one or more of the biological activities of bradykinin have been described among compounds as diverse as analgesics and anti-inflammatory substances, which act via the prostaglandin system and not directly on bradykinin biological receptors (Rocha e Silva and Leme, Med. Exp, 8:287, 1963). These are antihistamines (Geese et al, J. Phar . Pharmacol. 21: 544, 1969) ; bradykinin-antibodies (Grez et al, Eu. J. Pharmacol. 29:35, 1974) ; benzodiazepine derivatives (Leme and Rocha e Silva, Br. J. Pharmacol. 25:50, 1965); high molecular weight ethylene oxide polymers (Wilkens and Back, Arch. Intl. Pharmacodynam. 209:305, 1974) ; gallic acid esters (Posati et al., J. Agri. Food Chem. 18:632, 1970) and serotonin inhibitors (Gomazkon and Shimkovich, Bull. Exptl. Biol. Med. 80:6, 1975). None of these individual compounds or classes of compounds specifically inhibit bradykinin. Heptyl esters of various amino acid-containing substances, such as single basic amino acids (ie. Arg and Lys) (Geese, Adv. Exptl. Biol. Med. 70:5, 1976), the dipeptide Phe-Gly (Geese et al. Int. Aech. Allergy 41:174, 1971), and of analogs of C- terminal peptide fragments of bradykinin (ie, Pro-Phe-Arg) (Claesson et al.. Adv. Exptl. Med. Biol. 120B: 691, 1979) have been reported as anti-bradykinin substances. When tested in bradykinin assay systems they prove to be weak partial agonists/antagonists, depending on the dose, with little specificity for inhibiting bradykinin action. Preparations of damaged vascular tissue have been . reported to respond to bradykinin analogs which lack the C- terminal Arg residue, but not to bradykinin itself, and analogs of these des-Arg 9-bradyk ins have been developed as antagonists of this non-physiological activity of bradykinin. These antagonists have no significant bradykinin-like agonist effects, nor any antagonist effect on any of the physiologically significant kinin-responding systems (Regoli and Barabe, Pharmacol. Revs. 32:1,1980). Several bradykinin analogs containing the O-methyl ether of Tyr residues at positions 5 and/or 8 have been reported to produce mixed agonist/antagonist activity on isolated uteri of galactosemic rats, but not on normal rats. The antagonism was not reliably reproducible in these animals (Stewart and Woolley, in Hypotensive Peptides, Springer Verlag, pp. 23-33, 1966). Other changes in the bradykinin molecule have been additions of amino acids at the N-terminal end which affect the rate of enzymatic degradation of bradykinin in vivo. The half life of bradykinin in the systemic circulation is less than 30 seconds (S.H. Ferreira & J.R. Vane, Br. J. Pharmacol. Chemotherap. 30:417, 1967). Bradykinin is completely destroyed (98-99% destruction) on a single passage through the pulmonary circulation (J. Roblero, J.W. Ryan and J.M. Stewart, Res. Com un. Pathol. Pharmacol. 6:207, 1973) as determined in the anesthetized rat by measuring the depressor effects of an agonist following intra-aortic (IA) (bypassing the pulmonary circulation) and intravenous (IV) administration. Resistance of bradykinin agonists to pulmonary kininase destruction is vivo is promoted by addition of single (ie, DArg-, DLys-, Lys-) and double (DLys-Lys-) basic amino acid residues to the N-terminal of the bradykinin sequence. The addition of the dipeptide Lys-Lys to the N-terminal of bradykinin agonists confers complete resistance to in vivo destruction on initial passage through the pulmonary circulation (Roblero, Ryan and Stewart, Res. Comm. Pathol. Pharmacol . 6 : 207 , 1973 ) . SUMMARY OF INVENTION The invention relates to the modification of the sequence of the mammalian peptide hormone bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) and pharmaceutically acceptable salts thereof, at the Pro residue at position 7 in a unique manner which, produces sequence-related analogues that act as specific and competitive inhibitors of the biological activities of bradykinin. The invention specifically relates to the substitution of the L-Pro at position 7 with substituted and unsubstituted aromatic amino acids of the D-configuration, a change which converts bradykinin agonists into antagonists, and includes additional modifications at other positions within the 7-position modified bradykinin antagonist which confer increased antagonist potency, resistance to enzymatic degradation and/or tissue specificity on the D-amino acid-containing bradykinin sequence. The invention further includes the necessary substitution of L-Pro at position 7 with substituted and unsubstituted amino acids of the D configuration together with the substitution of arginine in the one and nine positions with D or L-cyclic (heterocyclic or alicyclic) , aliphatic amino acid residue. The invention also includes the necessary substitution of L-Pro at position seven to provide bradykinin antagonists lacking an alpha amino group or having a beta amino acid residue alone or together with sequence deletions or terminal extensions. More specifically, the invention relates to the peptides of the general formula: Formula I N-Al-B-C-D-W-X- Y-Z -A9 (0 1 2 3 4 5 6 7 8 9 ) (position number) Wherein N is a hydrogen atom or single acidic, basic, neutral or aromatic amino acid residue of the D- or L- configuration, such as D-Arg, D-Lys or L-Thi, an N-terminal enzyme protecting group from the group comprising acyl-type protecting groups, Λirethane-type protecting groups, alkyl-type protecting groups, or alternately N is a di- or poly-peptide containing amino acids of the D- or L- configuration, such as Lys-Lys, Met-Lys, or Gly-Arg-Met-Lys; Al lacks an alpha amino group or Al and A9-are either or both an Arg residue or other cyclic (heterocyclic or alicyclic) amino acid residue, aliphatic amino acid residue or an aromatic or substituted aromatic amino acid residue of the D or L configuration; B is D- or L-Pro residue, or other D- or L-cyclic (hetero or alicyclic) or noncyclic aliphatic amino acid residue, such as L-hydroxyproline, or a substituted or unsubstituted beta amino acid residue of the D- or L-configuration or a D- or L-aromatic or substituted aromatic amino acid residue or wherein B is deleted; C is D- or L-Pro residue, or other cyclic (heterocyclie or alicyclic) , aliphatic, aromatic or substituted aromatic amino acid residue of the D- or L-configuration or wherein C is deleted; D is a Gly residue or other aliphatic, aromatic or substituted aromatic amino acid residue of the D- or L-configuration, such as Ala, or wherein D is deleted; W is a Phe residue of the L-configuration, or a substituted Phe or other aliphatic or aromatic amino acid residue of the D or L configuration, such as Leu, beta-2-thienyl-alanine (Thi) or 2-pyridyl-alanine (Pal) ; X is a Ser residue of the D- or L-configuration, a Gly residue, or other aliphatic, cyclic, aromatic or substituted aromatic amino acid residue of the D- or L-configuration, such as pCl-D-Phe or D-Phe; Y is a D-aromatic amino acid residue, or substituted aromatic amino acid residue, such as D-Phe, beta-(2-thienyl)-D Ala (DThi), beta-(2-pyridyl)-D-Ala (D-Pal) , β-2-naphthyl-D Ala (D-Nal) , DHis, D-homo-Phe (DhPhe) , O-methyl-DTyr (DOMT) , D-alphaphenyl-Gly (DPhg) , DTrp, DTyr or pCl-DPhe (CDF) ; Z is a Phe residue of the L-configuration, or a substituted Phe or other aliphatic or aromatic amino acid residue of the D- or L-configuration, such as Leu, Thi or Pal or a cyclic amino acid such as a D- or L-Pro. In a preferred compound of the general formula I the substituents have the following identity: A = H, B = Pro or Hyp, C = Pro or Hyp, D = Gly, W = Z = Phe or Thi, X= Ser and Y = any aromatic amino acid of the D-configuration. Salts of peptides of general formula I include salts with HC1, TFA, AcOH, as well as other pharmaceutically acceptable salts. The following TABLES I and II show substitutions that can be made in the bradykinin polypeptide and the effect of such substitutions. Indicated substitutions of the 0, 1, 2, 3, 5, 7 and 8 amino acid residues of bradykinin yield preferred bradykinin antagonists. TABLE I SUBSTITUTIONS IN BRADYKININ ANTAGONISTS Arg DArg DPhe DThi Phe Arg DArg DPhe DThi FDF=p-Fluorophenylalanine Phe bAla=β-Alanine DPal Thi= /3-(2-Thienyl)alanine DNal Pal= β-(2-Pyridyl)alanine CDF Hyp=4-Hydroxyproline DTyr Azt=Azetidine-2-carboxylic acid FDF Thz=Thiazolidine-2-carboxylic acid DTrp Inip=Isonipecotic acid DVal OMT=0-Methyltyrosine Dlle CDF=para-chloro-D-phenylalanine Bz Nal= β-(2-Naphthy1)-alanine PBA CLF=para-chloro-L-phenylalanine He PNF=para-nitrophenylalanine ΔPro=2, 3-Dehydroproline PBA=4-phenylbutyric acid Des=the residue normally in this position in bradykinin is missing Bz=Benzoyl DHP=3,4-Dehydroproline TABLE II CHARACTERISTICS OF BRADYKININ ANTAGONISTS Changes confer Critical change for tissue selectivity Antagonist activity \\ A—Pro— ro—Gly—Phe—Ser—P >rroo- Addi ytions confer Alteration enhances enzyme resistance potency DETAILED DESCRIPTION The synthesis of the peptides of general Formula I, including derivatization, activation, and coupling of protected amino acid residues, and their purification, and the analytical methods for determining identity and purity are included in the general body of knowledge of peptide chemistry, as described in Houben Weyl "Methoden der Organische Chemie M Vol. 16, parts I & II (1974) for solution-phase synthesis, and in "Solid Phase Peptide Synthesis" by Stewart and Young (1984) for synthesis by the solid-phase method of Merrifield. Any chemist skilled in the art of peptide synthesis can synthesize the peptides of general Formula I by standard solution methods or by manual or automated solid-phase methods. The symbols and abbreviations used for amino acids, their derivatives and protecting groups, and peptides and their salts are those customarily used in peptide chemistry (Biochem. J. 126:773, 1972, the Journal reference is hereby incorporated by reference) . For convenience several abbreviations are defined in Table III reproduced below. All amino acid residues, except Gly, described in the specification (but not the claims which claims cover compositions of the D- and L-configuration) are of the L-configuration unless otherwise specified. TfrBfcE III ABBREVIATIONS FOR AMINO ACID RESIDUES Aib - alpha-aminoisobutyric acid Ala - alanine bAla - beta-alanine Azt - azetidine-2-carboxylic acid CDF - para-chloro-D-phenylalanine CLF - para-chloro-L-phenylalanine DHP - 3,4 dehydroproline FDF - para-phenylalanine-D-phenylalanine hPhe - homo-phenylalanine His - histidine Hyp - 4-hydroxy-proline Gly - glycine He - isoleucine Inip - isonipecotic acid Leu - leucine MDY - O-methyl-D-tyrosine OMT - O-methyl-tyrosine Nal - beta-(2-naphthyl)-alanine APro - 2,3-dehydroproline Pal - beta-(3-pyridyl)-alanine or Z pyredyl Phg - alpha-phenylglycine Phe - phenylalanine TABLE III, Cont'd ABBREVIATIONS FOR AMINO ACID RESIDUES PNF - para-nitro-phenalanine Sar - sarcosine Thi - beta-(2-thienyl)-alanine Thz - thiazolidine-2-carboxylic acid Tyr - tyrosine (all other abbreviations follow the IUPAC standards for amino acid residues) The following examples are illustrative of compounds of this invention with general formula I and are not limitative. All percentages and ratios are by weight when solids are involved and by volume when only liquids are involved. EXAMPLE 1 Preparation of Arg-Pro-Pro-Gly-Phe-Ser-DPhe-Phe- Arg (DPhe 7 -BK) . A mixture of 6.4 g of tertiary butyloxy carbonyl- (g-paratoluene sulfonyl)-Arg [Boc-Arg(Tos) ] (15mMole) and 183 mg of N, N-dimethylaminopyridine (1.5mMole) was dissolved in a mixture of 20 ml of dimethylformamide (DMF) and 125 ml of dichloromethane (DCM) . Fifteen g (grams) of hydroxymethyl-polystyrene- divinyl benzene (1% crosslinked, containing 0.74 mMole of free hydroxyl group per g of resin) was added, followed by 60 ml of a 0.25 M solution of dicyclohexylcarbodiimide (DCC) in DCM at room temperature. The suspension was stirred at room temperature overnight, filtered, and the resin was washed three times with 60 ml of DCM, three times with 60 ml of methyl alcohol (MeOH) , and reswollen in 120 ml of DCM. The coupling of another portion of Boc-Arg(Tos) was conducted on the resin as above. After filtering and washing the resin it was reswollen in 120 ml of DCM, and 2.1 ml of benzoyl chloride and 1.5 ml of triethylamine (Et_N) were added. After stirring the suspension for 30 minutes at room temperature the resin was filtered, washed three times with 60 ml portions of DCM, MeOH, washed three times with 60 ml portion of MeOH and finally washed three times with 60 ml portions of DCM. The resin was air dried to constant weight to give 18.5 g of Boc-Arg(Tos) -hydroxymethyl-resin, with an actual amino acid content of 0.272 millimoles of Arg per g of resin as determined by quantitative amino acid analysis of a sample of the amino acid resin following hydrolysis (4 hr, 130 degrees C) in 6 N HCL/propionic acid. The resin, 1.5 gm containing a total of 0.4 mMole of Arg, was placed in the reaction vessel of an automatic solid-phase synthesizer (Beckman model 990) and subjected to one cycle of addition for the coupling of Boc-Phe as follows; PROGRAM A. STANDARD DCC COUPLING: The resin was washed three times with 20ml portions of DCM. The resin was then equilibrated with 20ml of a 1:3 ratio of trifluoroacetic acid (TFA) in DCM containing 0.1% indole for 1.5 minutes. The equilibration was then repeated for 30 minutes. The resin was then washed six times with 20ml portions of DCM followed by neutralization with a 10% solution of (Et 3 N) in DCM for one and one half minutes, then the neutralization step was repeated. The resin was washed six times with 20ml of DCM and then equilibrated with a solution of 1.0 Mole of Boc-Phe in DCM for one and one half minutes. Then four ml of 0.25 N DCC in DCM was added and the mixture stirred for two hours. Then the resin was washed three times with 20ml portions of DCM. A second cycle of addition was performed according to Program B: PROGRAM B. REVERSE ADDITION: The procedure of Program A through neutralization and following washes was repeated. Then 1.0 mMole of DCC in 4ml of DCM was added and the resin and solution were mixed for one and one-half minutes. Then 1.0 mMole of Boc-D-Phe in 12ml DCM was added and the resin and solution were mixed for two hours. The resin was then washed six times with 20ml portions of DCM. The N-Terminal protecting group was removed according to the following sequence: PROGRAM C. TERMINAL DEPROTECTION: The procedure of PROGRAM A up to the neutralization with triethylamine was repeated. The resin was then washed 6 times with 20ml portions of ethyl alcohol and the peptide-resin was air dried giving 1.66 gm of DPhe-Phe-Arg-Resin as the trifluoroacetic acid salt. Synthesis was continued with 410 mg of the DPhe- Phe-Arg-Resin TFA salt. The next residue was added according to PROGRAM D. PROGRAM D. RECOUPLE: The peptide-resin salt was first washed three times with 20ml portion of DCM, then neutralized with 10% Et_N DCM for 1.5 minutes. The neutralization step was then repeated and the peptide-resin-salt was washed six times with 20ml portions of DCM. The peptide-resin was then equilibrated with a solution of 1.0 mMole of Boc-Ser(OBzl) in DMF for 1.5 minutes. Four ml of 0.25 N DCC in DCM was added and mixed with the resin for two hours. The product was washed three times with DCM. The following amino acid derivatives were added to the growing peptide chain according to the listed Programs: Boc-Phe (A) , Boc-Gly (A) , Boc-Pro (A) , Boc-Pro (A) , followed by recouple of Boc-Pro (D) , Boc-Arg(Tos) (dissolved in 2 ml DMF + 9 ml DCM) , (A) , followed by Program C. This gave 530 mg of protected nonapeptide-resin as the TFA salt. A 510 mg portion of the peptide-resin above was suspended in 10 ml of liquid anhydrous HF containing 1 ml of anisole at -70 degrees C and stirred 45 min. at 0 degrees C. HF and anisole were removed by vacuum (1 hr water pump, 1 hr vacuum pump) , the peptide plus resin was washed three times with 20ml portions of ethyl ether (Et 2 0) and the peptide extracted into glacial acetic acid using three 6 ml extractions. The acetic acid solution was lyophilized to give 185 mg of crude deprotected peptide. The peptide was purified by countercurrent distribution (CCD) (100 upper phase transfers in a Post CCD apparatus) in the solvent system nBuOH:l% TFA (1:1). The content of the tubes corresponding to the main peptide- containing peak, as determined by the quantitative Sakaguchi reagent, was collected, the solvent evaporated under reduced pressure, the residue dissolved in glacial acetic acid (AcOH) and lyophilized to give 140 mg of peptide with a partition coefficient (k) from the CCD of 5.7. Repeating the countercurrent distribution in the solvent system nBuOH:AcOH:H 2 0 (4:1:5) gave, upon detection and workup as described above, 73 mg of Arg-Pro-Pro-Gly-Phe-Ser-DPhe-Phe-Arg as the TFA salt (k = 0.2). Thin layer chromatographs (TLC) on Merck glass precoated silica gel plates in the solvent systems nBuOH:AcOH:H Λ,_*0 (8:3:4) and EtOAc:pyridine:AcOH:H £„*0 (5:5:1:3) gave Rf(834) of 0.17 and Rf(5513) of 0.36 for the pure peptide, as visualized by the chlorine-tolidine peptide identification spray. Quantitative amino acid analysis (Beckman 120 instru ent) after acid hydrolysis (17 hr in sealed glass vials under N, at 110° C in 2 ml 6 N HC1 containing 2 drops 2-mercaptoethanol and 40 icroliters of phenol) gave the following ratios of amino acids: Arg(2.12); Pro(1.93); Gly(l.Ol); Phe(2.98); Ser(0.96). EXAMPLES 2 - 4 BRADYKININ PEPTIDE ANTAGONISTS LACKING THE ALPHA-AMINO GROUP Examples 2 - 4 of the invention relate to novel modifications of the bradykinin (BK) sequence (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in which the N-terminal of BK antagonist sequences are modified by removal of the alpha-a ino group and include a D amino acid at position 7.. Such modified BK analogs, referred to as desamino-antagonists, exhibit antagonism of BK-induced pharmacological responses, and represent a new class of BK-related peptide antagonists. The literature reports that desamino-BK possesses about 20% of BK agonist potency on smooth muscle. The BK antagonist peptides described in our copending parent U.S. Application S.N. 744,207 filed June 13, -1985, possess amino acid or peptide extensions at the N-terminus, and in all cases, except for acetyl-blocked antagonist analogs, possess a free amino group. The modifications of BK antagonist sequences at the N-terminal alone or together with the desamino-antagoniεts of Examples 8 - 24 represent novel BK antagonists with biological and therapeutic potential. Examples 2 - 4 represent bradykinin antagonists lacking an alpha amino group and containing a D-hydrophobic amino acid residue at position seven with or without a sequence deletion at other positions in the bradykinin antagonist which were prepared by methods similar to those described in Example 1. 2. Bz-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg (Bz 1 Hyp 3 DPhe 7 -BK) : k (415) = 6.14 Arg - 1.06, Pro - 1.01, Gly - 1.05, Phe - 3.02, Ser - 0.93, Hyp - 0.93. 3. PBA-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg (PBA 1 Hyp 3 DPhe 7 -BK) : k (415)=9.00 Arg - 1.08, Pro - 0.96, Gly - 1.08, Phe - 3.02, Ser - 0.99, Hyp - 0.86. 4. PBA-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg [ (PBA 1 -(des-Pro 2 )-Hyp 3 DPhe 7 -BK)]: k(415) = 9.00, Arg - 1.08, Gly - 1.04, Phe - 3.05, Ser - 0.94, Hyp - 0.89. EXAMPLES 5 - 8 Examples 5 - 8 represent bradykinin antagonist containing beta amino acid residues with a D-hydrophobic amino acid residue at position 7 with or without a sequence deletion at other positions in the bradykinin antagonist which were prepared by methods similar to those described in Example 1. 5. Arg-bAla-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg (bAl 2 Hyp 3 DPhe 7 -BK) : k(l:l) = 2.030, Arg - 2.10, Gly - 0.96, Phe - 3.00, Ser - 1.00, Hyp - 0.94, bAla. 6. DArg-Arg-bAla-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg (DArg°bAla 2 Hyp DPhe 7 -BK) : k(415) = 0.124, Arg - 2.14, Gly - 1.00, Phe - 2.98, Ser - 0.86, Hyp - 1.01, bAla - 2.08. 7. Arg-bAla-Gly-Phe-Ser-DPhe-Phe-Arg [ (bAla 2 -(des-Pro 3 )-DPhe 7 -BK)]: k(415) = 0.235, Arg - 2.14, Gly - 1.01, Phe - 2.96, Ser - 0.90, bAla - 0.99. 8. DArg-Arg-bAla-Gly-Phe-Ser-DPhe-Phe-Arg [(DArg 0bAla2(des- Pro 3 )-DPhe 7 -BK) ] : k(l.l) = 2.846, Arg - 3.04, Gly - 1.05, Phe - 2.94, Ser - 0.96, bAla - 1.90. EXAMPLES 9 - 19 Examples 9 - 19 represent deletion analogs of bradykinin antagonist peptides possessing bradykinin antagonist activity which were prepared by methods similar to those described in Example 1. 9. Arg-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg [(des-Pro 2)-Hyp3DPhe7 -BK)]: k(415) = 0.235 ' , Arg - 2.13, Gly - 1.05, Phe - 3.02, Ser - 0.93, Hyp - 0.87. 10. DArg-Arg-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg [ (DArg 0 -(des-Pro 2 ) -Hyp 3 DPhe 7 -BK) ] : k(415) = 0.266, Arg - 3.09, Pro - 1.00, Gly - 0.96, Phe - 4.04, Ser - 0.91. 11. Arg-Gly-Phe-Ser-DPhe-Phe-Arg [ (des-Pro 2 /3 )-DPhe 7 -BK) ] : k(l.l) » 5.250, Arg - 2.14, Gly - 1.00, Phe - 2.93, Ser - 0.93. 0 2 3 12. DArg-Arg-Gly-Phe-Ser-DPhe-Phe-Arg [(DArg -(des-Pro ' ) -DPhe 7 -BK)]: k(l.l) = 3.762, Arg - 3.16, Gly - 0.16, Phe - 2.88, Ser - 0.90. 2 3 4 13. Arg-Hyp-Phe-Ser-DPhe-Phe-Arg [(des-Pro )Hyp (des-Gly ) -DPhe 7 -BK)]: k(l.l) = 4.263, Arg - 2.12, Ser - 0.97, Hyp - 0.92, Phe - 2.99. 3 2 7 14. Arg-Phe-Gly-Phe-Ser-DPhe-Phe-Arg [(des-Pro )-Phe DPhe -BK)]: k(415) « 0.515, Arg - 2.09, Gly - 1.02, Ser - 0.99, Phe - 3.99. 0 3 15. DArg-Arg-Phe-Gly-Phe-Ser-DPhe-Phe-Arg [(DArg -(des-Pro ) -Phe 2 -DPhe 7 -BK) ] : k(415) = 0.961, Arg - 2.35, Gly - 1.20, Phe - 3.96, Ser - 0.83. 16. Arg-bAla-Gly-Phe-Ser-DPhe-Phe-Arg [ (bAla-(des-Pro 3 )-DPhe 7 -BK)]: k(415) = 0.235, Arg - 2.14, Gly - 1.01, Phe - 2.96, Ser - 0.90, bAla - 0.99. 17. DPhe-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg [ (DPhe 1 -(des-Pro 2 )-Hyp 3 DPhe 7 -BK) ] : k(415) = 1.381, Arg - 1.00, Gly - 1.07, Ser - 1.04, Phe - 3.97, Hyp - 0.93. 18. DNal-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg [ (DNal 1 -(des-Pro 2 )-Hyp 3 DPhe 7 -BK)]: k(415) = 0.461, Arg - 1.03, Gly - 1.07, Phe - 3.17, Ser - 0.96, Hyp - 0.91, Nal - 0. 1 2 3 19. DArg-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg [(DArg -(des-Pro )-Hyp DPhe 7 -BK)]: k(415) = 0.266, Arg - 2.13, Gly - 1.06, Phe - 2.99, Ser - 0.91, Hyp - 0.92. EXAMPLES 20 - 23 BRADYKININ PEPTIDE ANTAGONISTS POSSESSING AN AROMATIC AMINO ACID RESIDUE AT POSITION NINE IN PLACE OF ARGININE AS WELL AS SEQUENCE DELETIONS Examples 20 - 23 of the invention relate to novel modifications of the bradykinin (BK) sequence (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) having the critical 7 position substitution in which the C-terminal arginine residue of BK antagonist sequence is replaced by an aromatic amino acid residue, and in addition an amino acid residue is deleted within the sequence. Such modified BK analogs exhibit antagonism of BK-induced pharmacological responses and represents a new class of BK-related peptide antagonists. The BK antagonist peptides described in our copending parent U.S. Application S.N. 744,207 filed June 13, 1985 possess an Arg residue at the C-terminus of nonapeptide BK-sequences. The present modifications of BK antagonist sequences represent novel BK antagonists with biological and therapeutic potential. Examples 20 - 23 represent bradykinin antagonist peptides possessing a C-terminal phenylalanine (Phe) . Peptide analogs possessing a C-terminal Phe residue are prepared by methods described in the Example 1 for the preparation of [DPhe ]-BK, except that the starting amino acid resin is Boc-Phe-hydroxymethyl-Resin (Boc-Phe-HMR) , which is prepared similarly to Boc-Arg(Tos)-HMR above. Boc-Phe (1.325 g (5 mMole) and 61 mg (0.5 mMole) p-dimethylaminopyridine (DMAP) are added to 5.0 g hydroxymethyl-polystyrene-divinylbenzene (1% crosslinked) in 80 ml DCM. To this is added 5 ml of 1.0 M DCC in CHC1_, and the mixture is stirred 3.5 hr. The mixture is filtered and the amino acid resin is washed thoroughly with DCM, EtOH, and DCM, suspended in 80 ml DCM at 0 degrees, and treated with a mixture of 4.4 ml benzoyl chloride (37.5 mM) and 3.8 ml pyridine (47 mM) for 15 min., followed by 5 hr. stirring at room temperature. The resin is filtered, washed with DCM and air dried to give 5.5 g Boc-Phe-HMR, containing 0.485 mMole of Phe per gram of resin, as determined by quantitative amino acid analysis. Examples 20 - 23 represent bradykinin antagonist peptides possessing an aromatic amino acid residue at position nine in place of arginine and sequence deletions. The bradykinin antagonist peptides were prepared by methods similar to those described for Example 1. 20. Arg-Hyp-Gly-Phe-Ser-DPhe-Phe-Phe [ (des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 -BK) ] : k(415) = 1.632, Arg - 1.03, Gly - 1.06, Ser - 0.87, Hyp - 0.94, Phe - 4.09. 21. D-Arg-Arg-Hyp-Gly-Phe-Ser-DPhe-Phe-Phe [(D-Arg 0-(des-Pro2) -Hyp 3 DPhe 7 Phe 9 -BK) ] : k(415) =» 0.515, Arg - 2.05, Gly - 0.99, Phe - 3.96, Ser - 0.97, Hyp - 1.02. 22. D-Arg-Hyp-Gly-Phe-Ser-DPhe-Phe-Phe [ (DArg 1 -(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 -BK) ] : k(415) = 1.564, Arg - 1.00, Gly - 1.03, Ser - 0.93, Hyp - 1.04, Phe - 3.99. 23. DArg-DArg-Hyp-Gly-Phe-Ser-DPhe-Phe-Phe [(DArg ' -(des- Pro 2 )-Hyp 3 DPhe 7 Phe 9 -BK) ] : k(415) = 0.538, Arg - 2.08, Gly - 0.94, Phe - 4.05, Ser - 0.91, Hyp - 1.02. EXAMPLES OF BRADYKININ ANTAGONIST ACTIVITY The bradykinin antagonists were assayed on isolated rat uterus in natural or induced estrus and on guinea pig ileum, according to the commonly accepted assay methods for bradykinin and related kinins as described by Trautschold (Handbook of Expt. Pharmacol. Vol 25, Springer Verlag, pp. 53-55, 1970) for inhibition of the myotropic activity of bradykinin. The inhibition potencies, as determined according to the commonly accepted manner described by Schild for antagonists of biologically active compounds (Br. J. Pharmacol. 2:189, 1947), and expressed as p „ values are determined on isolated rat uterus (RUT) and isolated guinea pig ileum (GPI) . In the assays, a dose-response curve is determined for the reference substance bradykinin. The dose of bradykinin which produced a half maximal contraction of tissue is the ED ς _ dose. An amount of bradykinin equivalent to twice the ED 5Q dose is administered to the tissue 30 seconds after the start of incubation of the tissue with a dose of antagonist. Doses of antagonist are increased in this protocol until pre-incubation with a dose of antagonist reduces the contraction in response to the double ED 50 dose of bradykinin to response of a single ED 5 dose of bradykinin. The p 2 value represents the negative logarithm of the molar concentration of antagonist necessary to reduce the response of a double ED 5Q dose of bradykinin to that of an ED > 5f0 dose. One unit of pA 2 value represents an order of magnitude change in potency. For comparison, the negative log of the dose of BK, the dose which causes half maximal contraction of the tissues, is commonly known as the pD_ value. The pD 2 value for bradykinin is 7.9 on the rat uterus and 7.4 on the guinea pig ileum. The values for compounds of various Examples are reported in Table IV. TABLE IV POTENCY OF BRADYKININ ANTAGONISTS EXAMPLE STRUCTURE p 2 /RU pA 2 /GPI 2. (Bz 1 Hyp 3 DPhe 7 )-BK 0 5.4(4) 3. (PBA 1 Hyp 3 DPhe 7 )-BK 0/1 0 4. (PBA 1 -(des-Pro 2 )-Hyp 3 DPhe 7 )-BK 0 5.2m TABLE IV, Cont'd POTENCY OF BRADYKININ ANTAGONISTS EXAMPLE STRUCTURE p 2 /RUT A 2 /GPI 5. (bAla 2 Hyp 3 DPhe 7 )-BK 0 0 6. DArg-(bAla 2 Hyp 3 DPhe 7 )-BK 0 0 7. [bAla 2 -(des-Pro 3 )-DPhe 7 ]-BK 0 0 8. DArg-[bAla 2 -(des-Pro 3 )DPhe 7 ]-BK 0.05% 5.4(3) 9. [(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 0 0 10. DArg-[ (des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 5^(9) 11. [(des-Pro 2 ' 3 )-DPhe 7 ]- BK 0 12. DArg-[(des-Pro 2 ' 3 )-DPhe 7 ]- BK 0.08% 1 0 13. [ (des-Pro 2 -Gly 4 )-Hyp 3 DPhe 7 ]-BK 0 14. [ (des-Pro 3 )-Phe 2 DPhe 7 ]-BK 0 0 15. DArg-[ (des-Pro 3 )-Phe 2 DPhe 7 ]-BK 5^(7) 16. [bAla 2 -(des-Pro 3 )-DPhe 7 ]-BK 0 17. [DPhe 1 -(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 0 18. [DNal 1 -(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK TABLE IV, Cont'd POTENCY OF BRADYKININ ANTAGONISTS EXAMPLE STRUCTURE pA 2 /RU pA 2 /GPI NO. ; 19. [DArg 1 -(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 20. [(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 ]-BK 21. DArg-[(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 ]-BK 22. [DArg 1 -(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 ]-BK 23. DArg-[DArg 1 -(des-Pro 2 )-Hyp 3 DPhe 7 he 9 ]-BK Biological activity is listed for the analogs on rat uterus (RUT) , and guinea pig ileum (GPI) . Agonist potency is listed as percent of BK potency. Antagonist potency is listed as the p 2 value and is underlined, followed in parentheses by the number of tissues in the determination. I/O indicates analog exhibits both antagonism and no effect on separate tissues in screening assays. EXAMPLE OF SPECIFICITY OF KININ ANTAGONISM ON SMOOTH MUSCLE The specificity of bradykinin antagonists of this invention is demonstrated by their ability to inhibit the myotropic activity of bradykinin (BK) and two physiologically important BK-related kinins, kallidin (KAL, Lys-BK) and methionyl-lysyl-BK (MK-BK) , but not the myotropic activity induced by non kinin-related peptides, such as angiotensin-II (ANG) or substance-P (SP) . In each case, as shown, the BK-related antagonists inhibited contractions produced by BK-related agonists, but had no effect on the non-kinin myotropic peptide substances. The inhibition potencies are listed as pA2 values as described above in Table IV. EXAMPLE OF THE ANTAGONISM OF BRADYKININ ANTAGONISTS ON RAT BLOOD PRESSURE The n vivo effects of bradykinin antagonists on blood pressure in the anesthetized rat are determined according to the assay described by Roblero, Ryan and Stewart (Res. Commun. Pathol. Pharmacol. 6:207, 1973). The antagonists also produce inhibition of the bradykinin response when injected as a bolus admixture of bradykinin plus antagonist by either the ia or iv route of administration. The results of tests on compounds of various Examples are reported in Table V. TABLE V BRADYKININ ANTAGONISM ON BLOOD PRESSURE EXAMPLE NO STRUCTURE RBP-IA RBP-IV 2. (Bz 1 Kyp 3 DPhe 7 )-BK TABLE V, Cont'd BRADYKININ ANTAGONISM ON BLOOD PRESSURE EXftMP E NO STRUCTURE figp-ift. pgp-IV 3. (PBA 1 Hyp 3 DPhe 7 )-BK 0 0 4. [PBA 1 -(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 5. (bAla 2 Hyp 3 DPhe 7 )-BK 6. DArg-(bAla 2 Hyp 3 DPhe 7 )-BK 7. [bAla 2 -(des-Pro 3 )-DPhe 7 ]-BK 8. DArg-[bAla 2 -(des-Pro 3 )-DPhe 7 ]-BK 9. [(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 10. DArg-[(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 11. [(des-Pro 2 ' 3 )-DPhe 7 ]-BK 12. DArg-[(des-Pro 2 ' 3 )-DPhe 7 ]-BK 13. [(des-Pro 2 -Gly 4 )-Hyp 3 DPhe 7 ]-BK 14. [(des-Pro 3 )-Phe 2 DPhe 7 ]-BK 15. DArg-[ (des-Pro 3 )-Phe 2 DPhe 7 ]-BK 16. [bAla 2 -(des-Pro 3 )-DPhe 7 ]-BK 17. [DPhe 1 -(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 18. [DNal 1 -(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 19. [DArg 1 -(des-Pro 2 )-Hyp 3 DPhe 7 ]-BK 20. [(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 ]-BK 21. DArg-[(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 ]-BK 22. [DArg 1 -(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 ]-BK 23.DArg-[DArg 1 -(des-Pro 2 )-Hyp 3 DPhe 7 Phe 9 ]-BK Biological activity is listed for the analogs on rat blood pressure (RBP) following intra-aortic (IA) and intravenous (IV) bolus administration. IfP) indicates partial antagonism. I/O indicates analog exhibits both antagonism and no effect on separate animals. 1(B) indicates antagonism of BK-induced depressor effect. PRS indicates pressor effect. Therapeutic applications of the novel bradykinin antagonists include not only treatment for the production of bradykinin or related kinins by the animal but also the injection of bradykinin related peptides into an animal as a result of bites and stings. Topical application alone or in combination with subcutaneous utilization of the bradykinin antagonists of the invention can be employed to treat the effects of bradykinin-related peptides causing pain, inflammation and swelling. The therapeutic use of bradykinin antagonists of this invention for other traumatic, inflammatory or pathological conditions which are known to be mediated by bradykinin or exacerbated by an overproduction of bradykinin can also be achieved. These conditions include local trauma such as wounds, burns and rashes, angina, arthritis, asthma, allergies, rhinitis, shock, inflammatory bowel disease, low blood pressure, systemic treatment of pain and inflammation, and low sperm motility which produces male infertility. The present bradykinin antagonists, as discussed may be advantageously administered in a variety of ways including sublingual absorption as with nitroglycerine or patch administration using agents for assisting absorption through the skin such as for the treatment of angina. Based upon the PA 2 and ED 5Q data disclosed in this invention and in the prior art related to agonist potency, it is possible for one skilled in the art to make a determination of the dosage of the novel bradykinin antagonists of the invention. It is therefore estimated that the dosage range for typical application in such conditions as the pain and inflammation of wounds, burns and rashes would be 0.1 — 5mg/ml; for a nasal spray formulation suitable for treating rhinitis, allergies and asthma suitable dosage range would be 0.1 - 5 mg/ml; for intravenous formulation suitable for the treatment of. systemic inflammation, shock, arthritis, allergies, asthma; for an oral formulation for the treatment of inflammatory bowel disease or general pain and inflammation a suitable dosage range would be 10-100 mg/kg. Bradykinin antagonists can also be administered intravaginally, intrarectally, intrabuccally or any other accepted internal application. As will be recognized by those skilled in the art the present invention has a wide range of applicability to providing competitive inhibitors to the biological activities of bradykinin produced by the body in illness, injury and shock. The advantages of the invention in substituting the L-Pro position 7 with amino acids of the D-configuration to convert bradykinin agonists to antagonists provide a wide variety of specific and competitive antagonists for reducing the known effects of bradykinin. The additional advantages of the invention of modifying the L-Pro position 7 in conjunction with modifications at the other positions of the novel bradykinin antagonists provides a variety of useful compounds. It will further be appreciated the present invention is susceptible to these and other modifications within the parameters of the invention without departing from the scope of the following claims.

Claims: WHAT IS CLAIMED IS: 1 1. A substituted bradykinin type peptide of the 2 formula: 3 N-A1-B-C-D-W-X-Y-Z-A9 4 and the pharmaceutically acceptable salts thereof wherein 5 (a) N is hydrogen, an amino acid of the D- or L- 5 configuration, an N-terminal acyl type protecting group, an η N-ter inal aromatic urethane protecting group, an N-terminal g alkyl-type protecting group or a di or poly-peptide containi g an amino acid of the D- or L- configuration; 10 (b) Al is an amino acid of the L- or H D-configuration lacking an alpha amino group or is an 12 aliphatic, cyclic or aromatic amino acid of the D- or 13 L-configuration; 14 (c) B is a substituted or unsubstituted beta amino 15 acid residue of the D- or L-configuration or an aliphatic, Ig cyclic or aromatic amino acid of the D- or L- configuration o 17 wherein B is deleted; 2 (d) C is an aliphatic, cyclic or aromatic amino 19 acid of the D- or L- configuration or wherein C is deleted; 20 (e) D is an aliphatic, cyclic or aromatic amino 2i acid residue of the D- or L-configuration or wherein D is 2 deleted; 3 (f) W is an aliphatic, cyclic or aromatic amino 24 acid residue of the D- or L- configuration; 25 (g) X is an aliphatic, cyclic or aromatic amino 26 acid of the D- or L- configura ion; 27 ( ) Y is a D-aromatic ' mino acid residue or a 28 substituted D-aromatic amino acid residue; 29 (i) Z is an aliphatic, cyclic or aromatic amino 30 acid residue of the D- or L- configuration; and 31 (j) A9 is an aliphatic, cyclic or aromatic amino 32 acid residue of the D- or L-configuration. 1 2. The substituted bradykinin type peptide of cla * _? 1 wherei.n Al, C, D and A9 are an aliphatic, cyclic or aromat 3 amino acid residues of the D- or L-configuration. 3. The substituted bradykinin type peptide of cla 2 having the formula Arg-bAla-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg 4. The substituted bradykinin type peptide of clai 2 having the formula DArg-Arg-bAla-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg " 5. The substituted bradykinin type peptide of cla 2 wherein one or more of the positions B, C and D are desamino-BK positions. -- 6. The substituted bradykinin type peptide of cla 5 having the formula DArg-Arg-bAla-Gly-Phe-Ser-DPhe-Phe-Arg 7. The substituted bradykinin type peptide of cla • 1 wherein A9 is an aromatic amino acid residue and one or mo of the positions B, C and D are desamino-BK positions. 8. The substituted bradykinin type peptide of cla 7 having the formula DArg-DArg-Hyp-Gly-Phe-Ser-DPhe-Phe-Phe 9. The substituted bradykinin type peptide of cla 7 having the formula Arg-Hyp-Gly-Phe-Ser-DPhe-Phe-Phe 10. The substituted bradykinin type peptide of claim 7 having the formula DArg-Hyp-Gly-Phe-Ser-DPhe-Phe-Phe 11. The substituted bradykinin type peptide of claim 1 wherein Al lacks an alpha amino group. 12. The substituted bradykinin type peptide of claim 11 having the formula Bz-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg 13. The substituted bradykinin type peptide of claim 11 having the formula PBA-Pro-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg 14. The substituted bradykinin type peptide of claim 12 having the formula PBA-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg 15. The substituted bradykinin type peptide of claim 9 wherein one or more of the positions B, C and D are desamino-BK positions. 16. The substituted bradykinin type peptide of claim 1 wherein Al and A9 are an aliphatic, cyclic or aroma amino acid residues of the D- or L-configuration. 17. The substituted bradykinin type peptide of claim 16 wherein one or more of the positions B, C and D ar desamino-BK positions. 18. The substituted bradykinin type peptide of claim 17 having the formula DArg-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg 19. The substituted bradykinin type peptide of claim 17 having the formula DArg-Arg-Gly-Phe-Ser-DPhe-Phe-Arg -41- 20. The substituted bradykinin type peptide of claim 17 having the formula Arg-Pro-Phe-Ser-DPhe-Phe-Arg 21. The substituted bradykinin type peptide of claim 17 having the formula ' DArg-Hyp-Gly-Phe-Ser-DPhe-Phe-Arg 22. The pharmaceutical composition consisting essentially of the compounds as defined in claim 1 wherein enhanced resistance to enzymatic degradation is achieved b modifying the moiety A. 23. The pharmaceutical composition consisting essentially of the compounds as defined in claim 22 posses enhanced resistance to enzymatic degradation wherein A is D-Arg, D-Lys, Lys-Lys, L-Thi, Met-Lys or Gly-Arg-Met-Lys an the pharmaceutically acceptable salts thereof in combinatio with a pharmaceutically acceptable carrier. 24. The pharmaceutical composition consisting essentially of the compounds as defined in claim 1 wherein enhanced tissue selectivity is achieved by modifying the 4 moiety B alone or in combination with a modification of the 5 moiety C. 25. The pharmaceutical composition consisting 2 essentially of the compounds as defined in claim 24 possessi 3 enhanced tissue selectivity wherein B alone, C alone or a combination thereof are selected from a group comprising 5 L-Pro, L-hydroxyproline, ΔPro, D-valine, L-valine, g alpha-ammoisobutyric acid (Aib) , L-Ala, D-Ala, Sar, D-Gly, η L-Gly and the pharmaceutically acceptable salts thereof in g combination with a pharmaceutically acceptable carrier. 1 26. The pharmaceutical composition consisting 2 essentially of the compounds as defined in claim 1 wherein 3 enhanced potency is achieved by modifying the moiety W, X or alone or in combination. 27. The pharmaceutical composition consisting essentially of the compound as defined in claim 26 possessi enhanced potency wherein W alone or Z alone or in combinati are selected from a group comprising Phe, O-Methyl-Tyr(OMT) p-Chloro-Phe(CLF) , p-Nitro-Phe(PNF) , beta-2-naphthyl-Ala(NA Tyr, Thi, Pal, and the pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable carrier. 28. The pharmaceutical preparation for treating local pain and inflammation from burns, wounds, cuts, rashe and other such trauma and pathologic conditions caused by t production of bradykinin or related kinins by the animal wh comprises an effective amount of the compound of claim 1 sufficient to antagonize bradykinin and a suitable pharmaceutical carrier. 29. A process for treating local pain and inflammation which comprises administering an effective amount of the pharmaceutical preparation of claim 28 to a host. 30. The pharmaceutical preparation for treating -44- pain, inflammation and swelling from bites, stings or other injection of bradykinin or related kinins which comprises a effective amount of the compound of claim 1 sufficient to antagonize bradykinin and a suitable pharmaceutical carrier 31. A process for treating local pain, inflammat and swelling which comprises administering an effective amo of the pharmaceutical preparation of claim 30 to a host. 32. The pharmaceutical preparation for treating rhinitis and other such trauma and pathologic conditions comprising an effective amount of the compound of claim 1 a a suitable pharmaceutical carrier. 33. A process for treating rhinitis which compri administering an effective amount of the compound of claim to a host. 34. The pharmaceutical preparation for treating blood pressure and other such trauma and pathologic conditi caused by the production of bradykinin or related kinins by the animal which comprises an effective amount of the compo of claim 1 and a suitable pharmaceutical carrier. 35. A process for treating low blood pressure wh comprises administering an effective amount of the pharmaceutical preparation of claim 34 to a host. 36. The pharmaceutical preparation for treating asthma and other such trauma and pathologic conditions cause by the production of bradykinin or related kinins by the animal which comprises an effective amount of the compound o claim 1 and a suitable pharmaceutical carrier. 37. A process for treating asthma which comprises administering an effective amount of the pharmaceutical preparation of claim 36 to a host. 38. The pharmaceutical preparation for treating arthritis and other such trauma and pathologic conditions caused by the production of bradykinin or related kinins by the animal which comprises an effective amount of the compou of claim 1 and a suitable pharmaceutical carrier. 39. A process for treating arthritis which comprises administering an effective amount of the pharmaceutical preparation of claim 38 to a host.. 40. The pharmaceutical preparation for treating diarrhea and other such trauma and pathologic conditions caused by the production of bradykinin or related kinins by the animal which comprises an effective amount of the compou of claim 1 and a suitable pharmaceutical carrier. 41. A process for treating diarrhea which comprise administering an effective amount of the pharmaceutical preparation of claim 40 to a host. 42. The pharmaceutical preparation for treating irritable bowel syndrome and inflammatory bowel disease and other such trauma and pathologic conditions caused by the production of bradykinin or related kinins by the animal whi comprises an effective amount of the compound of claim 1 and suitable pharmaceutical carrier. 43. A process for treating irritable bowel syndrom and inflammatory bowel disease which comprises administering an effective amount of the pharmaceutical preparation of cla 42 to a host. 44. The pharmaceutical preparation for treating carcinoid syndrome and other such trauma and pathologic conditions caused by the production of bradykinin or related kinins by the animal which comprises an effective amount of the compound of claim 1 and a suitable pharmaceutical carrie 45. A process for treating carcinoid syndrome whi comprises administering an effective amount of the pharmaceutical preparation of claim 44 to a host. 46. The pharmaceutical preparation for treating pain associated with angina and other such trauma and pathologic conditions caused by the production of bradykinin or related kinins by the animal which comprises an effective amount of -the compound of claim 1 and a suitable pharmaceutical carrier. 47. A process for treating pain associated with angina which comprises administering an effective amount of the pharmaceutical preparation of claim 46 to a host. 48. The pharmaceutical preparation for treating pain and inflammation caused by the production of bradykinin or related kinins by the animal which comprises an effective amount of the compound of claim 1 and a suitable pharmaceutical carrier. 49. A process for treating pain and inflammation which comprises administering an effective amount of the pharmaceutical preparation of claim 48 to a host. 50. The pharmaceutical preparation for treating anaphylactic and septic shock and other such trauma and pathologic conditions caused by bradykinin or related kini in the animal which comprises an effective amount of the compound of claim 1 with a suitable pharmaceutical carrier. 51. A process for treating anaphylactic and sept shock which comprises administering an effective amount of pharmaceutical preparation of claim 50 to a host.

Inventors: STEWART JOHN M, VAVREK RAYMOND J, STEWART, JOHN, M., VAVREK, RAYMOND, J.
Applicants: STEWART JOHN M, VAVREK RAYMOND J, STEWART, JOHN, M., VAVREK, RAYMOND, J.
Application year: 1988
Main classification: A61K37
IPC codes: A61K38, A61P1, A61P9, A61P11, A61P17, A61P25, A61P29, A61P37, C07K7