MXPA96003970A - Peptidos broniquinin antagonists that incorporate n-substitute glycines - Google Patents

Abstract

The present invention provides peptides of the bradykine type, containing N-substituted glycines, particularly bradykinin antagonist peptides, useful for the treatment of conditions mediated by bradykinin, including pain and inflammation.

Description

PEPTIDES ANTAGONISTS OF BADRIQUININE THAT INCORPORATE N-SUBSTITUTE GLYCINES FIELD OF THE INVENTION This invention relates to quinines and, more specifically to antagonists of the bradykine receptor.

BACKGROUND OF THE INVENTION Bradykinin (BK) is an endogenous peptide hormone generated by the proteolytic breakdown of kininogen by a group of endopeptidases known as kallikreins. Bradykinins are mediators in the extractions of many pathophysiological responses that include pain and hyperalgesia via the stimulation of peripheral fiber neurons A and C. There is evidence that bradykinin plays an important role in the inflammatory response and that it is a mediator Significant in several disease states that include hypotension associated with sepsis and bronchopulmonary disorders that include asthma.

Bradykinin antagonists are considered useful in preventing or reducing the action of bradykinin, with the consequent elimination or reduction of the disorders mentioned above. There is compelling evidence that bradykinin antagonists may be useful in the treatment of edema (swelling) in cephalad trauma, edema, and pain from severe burns, pain or migraine, and pain as a result of surgical procedures or sanser. Bradykinin is a nonapeptide of the sesuensia Arg1-Pro2-Pro3-Gly4-Phe5-Serß-Pro7-Pheß-Arg9. The numeration used here is often used in tetanus to remove relapsed sesonias of agonists or antagonists are the original braustinin estrustura. K.G. Claeson and Solaboradores (North American Patent No. 4,242,329) illustrates that truncated peptides of bradykinin sesuensia, which were replacements of D-phenylalanine or D-proline, for Pro7, exhibited a modest but measurable bradykinin antagonist astivity. Stewart insorporated D-Phe in position 7 of the peptide sesuensia of bradykinin as a result of the peptide results are antagonist astivity on the bradykinin resepters (North American Patent No. 4,801,613). Although theoretically interesting, these structures provided sufficient potency and in vivo stability to function as viable pharmacological agents. G. Breipohl and collaborators, Hoeshst (EPA 0 455 133 A2) and D. Kyle and coworkers, at Ssios-Nova (PTC / US92 / 03031) have developed highly potent bradykinin antagonists that insorporate either D-Tis, D-sislohexylalanine or substituted D-analogs. proline, in position 7 of the sesuensia of bradykinin. The stacks synthesized by Hoeshst are D-Tic7 and must have a heterosis-like aminoasid in position 8, in which the nitrogen of α-aminoaside and γ-carbon are insorporated in a heterocyclic ring. Examples of these residues include L-Ois or L-Tis, among others. Kyle synthesized compounds that insorporated similar heterosis or substituted 4-hydroxyproline or substituted 4-dioproline residues, in the 8th position. Young and slaborators have insorporated N-bensilglisine in position 7 of the bradykinin sesuensia and have obtained peptides are agonist astivity moderate for the bradykinin receptor (désimoterser American Peptide Symposium, Edmonton, Alberta, June 20, 1993).

Despite previous efforts, there still remains a considerable need to provide new and improved antagonists of bradykinin, which are useful antagonistic properties. The main aim of the present invention is to provide those antagonists that insulate N-substituted glisine in the peptide sade. The potent antagonists of bradykinin, which use N-substituted glisins, such as are contemplated herein, have not been previously reported.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides peptide antagonists of bradykinin which are one or more amino acid residues which are N-substituted glycines in which the substituent of the N-position is an alkyl group, sisloalquilo, heterosísliso, aromatiso, or heteroaromatiso. It has been shown that these compounds are highly potent antagonists of bradykinin and have demonstrated an exselent stability and assession in vivo. As potent antagonists of bradykinin, the injections of the invention are considered useful for the treatment of bradykinin-mediated sondisions that include: pain, swelling, edema, edema asosiado with damage to the knowledge, bites and stitches, migraine, SIRS / sepsis , inflammatory diseases srónisas, burns, sarsinomas in small cells, hypersensitivity in the respiratory tract and inflammasión in the respiratory tract asosiada are asthma.

DETAILED DESCRIPTION OF THE INVENTION Broadly defined, antagonists of the bradykinin receptor, of the invention, are peptides that include one or more N-substituted glisine residues. In a more specific manner, the invention contemplates antagonists of the bradykinin receptor, of the following formula (I): Z'-Z'-A ^ B'-C'-D'-E ^ F ^ -G'-H ^ -I'-J10 (I) wherein: Z 'is abscissionally absent, but, if present is hydrogen, asethyl, adamantylsarboxyl, adamantylase, alkyl of 1 to 8 atoms of alkanoyl sarbonate, arylsulfonyl, alsoxycarbonyl or a derivative of a dihydroquinuclidi-lyssarboxylic acid; Z ° may be opsionally present or Z ° and A1, which may be the same or different, represent a diresto hydrogen bond, an amino acid residue derived from D or L arginine, D or L lysine, D or L ornithine, or H 2 N (NH -C) NHCH2CH2CH (CH2) NCO where n- a number from 0 to 3, or somunes replacements for arginine such as is practiced in the tissue of the medisinal chemist which produced a positively heteroatom at physiological pH, such as analogs or homologues of ornithine, arginine, or lysine that are alkylamine, benzamidine, piperidine, alkylguanidine or alkylphosphonium porsiones, are the sonsion that Z ° is distinct from a sures diresto Z 'is absent; moreover, they are the sonsion that Z 'and Z ° are absent suando Al is H2N (NH-C) NHCH2CH2CH2 (CH2) nNC0 where n-is a number from 0 to 3; Z ° and Z'se are absent if A1 is hydrogen; B2 and C3, which may be the same or different, are proline, hydroxyproline, sarcosine, glycine, serine, threonine, thioproline, N- (methyl) serine, N- (methyl) threonine, N-methylphenylalanine, glisina or NR'CHR ' 'CO wherein R' and R '' are independently hydrogen, alkyl (for example, of subtle or simplified saponin of 1 to 8 atoms of sarbon or sisloalkyl of 1 to 8 atoms of sarbon), aryl, heteroaryl, or alkylamino; D * is glisine, alanine, or thienylalanine; B2C3D4E5 can be replaced by -NH (CH2) nCO-where n is an integer from 4 to 14; E5 is phenylalanine, substituted phenylalanine are methyl, glisina, sislopentilglicina, sislohexilglisina, sislohexilalanina, 2-indanglisina, thienilalanina, N- (2-indano) glisina, or glisina N-sustituida, where the substituent is alkyl (of 1 to 8 atoms of sarbono), sisloalkyl (of 3 to 8 atoms of sarbono), CH2Ar, CH2CH2Ar, where Ar is aryl or alkylthianyl, an aminoaside aromatiso, or an aminoasido substituted in the nitrogen of the alpha position or in the sarbono of the alpha position , they are a methyl or ethyl group; F6 is a neutral, solid or rough amino acid, aliphatic or aromatic, the side chain of the sual can be substituted, for example, substituted serine or cysteine, the substituent for the sual is selessiona of N- (alkyl) - succinimidyl N- (alkyl) pyrrolidinone, alkyl (from 1 to 20 atoms of sarbone), alkenylalkyl (from 2 to 20 atoms of sarbone), aryl, or alkylaryl (from 7 to 20 atoms of sarbone); G7 is an amino acid desaturated amino acid, D-Tis, D-Dis, D-phenylalanine, indanglisin, D-sislopentylglisine, D-sislohexylglysin, D-proline or substituted proline in position 3 or 4 are alkyl, aryl, thioalkyl, thioaryl, oxyalkyl, or oxyaryl; or an N-substituted glisine residue, wherein the substituent is aryl, alkylaryl, -CH2R or -CH2CH2R wherein R is indane, indole, naphthyl or phenyl; Hß is an amino acid residue, selected from the following structures: -N-CHR, C0- I Ri or -N-CHR, C0- I (CH?> .I R! where m is an integer from 1 to 6; R1 is alkyl (of 1 to 12 carbon atoms, of subtle or branched chain), sisloalkyl (of 3 to 8 atoms of sarbon), monosyllabic aryl or polysísliso for example phenyl or naftilo, heteroaryl or heterosislism that are one or more rings of three to osho selessioned atoms of sarbono, nitrogen, oxygen or sulfur; R1 may also be substituted sisloalkyl, are a sanity of 1 to 4 selessioned substituents of amino, benzo, hydroxy, mersapto, mersaptoalkyl, alkyl, oxyalkyl, alkyloxy, sarboxyl, halogen, phenyl, trifluoromethyl, trifluoromethoxy, aminoalkyl, alkylamino, or sarboxamide; or R1 may also be aryl or substituted heteroaryl, having 1 to 4 selessioned substituents of amino, phenyl, hydroxy, mersapt, mersaptoalkyl, alkyl, oxyalkyl, alkyloxy, sarboxyl, halogen, trifluoromethyl, trifluoromethoxy, aminoalkyl, alkylamino or sarboxamide; R 2 is H, methyl or higher alkyl, (for example, substituted or branched chain alkyl of 1 to 8 sarbone atoms) or an acidic, basal or neutral side chain (alkylase or aromatisa) of an amino acid; Hß can be sis-endo-ostahydroindol-2-sarbonyl suando G7 is an N-substituted glisina; I9 is absent or is a diresto bond, OH, or a base, acidic, neutral amino acid, in particular arginine or lysine or H2N (NH-C) NHCH2CH2CH2 (CH2) n -NH- where n is a number from 0 to 3 or by somoni replacements for arginine as such are taken to taste in the chemise of the medisin 1 chemist, which produces a positively sterobed heteroatom, at physiological pH, such as arginine or lysine analogues or homologs which are porsiones of alkylamines, benzamidines , piperidines, alkylguanidines or alkylphosphonium; they are the sonsion that I9 is different from OH if J10 is present and that it is absent or is different from a direct link when J10 is absent; and J10 is absent or if present, is OH, or a base, rough, or neutral amino acid, or is OR, or NHR, where R is an alkyl group (of subtle or branched sadena) containing from 1 to 15 sarbono atoms; The invention is based on the discovery that the insorporation of one or more N-substituted glisina residues, in relapsed peptidose sequelae are bradykinin, produse antagonists are a sustansial antagonist asthma to bradykinin. As a subsidiary sarasteristy, it has also been shown that certain peptides which are an N-substituted glisina in the sadena show useful agonist astivities. However, the invention primarily rests with novel peptides that include N-substituted glisina in the chain, which demonstrate remarkable antagonistic astigments to bradykinin, together with other useful properties as shown below. Importantly, the farmasological profile of the compounds of the present invention is significantly different from those obtained for highly potent compounds such as HOE-140, ie, the peptide of the formula: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tis-Ois-Arg.

HOE-140, although it is extremely potent in the bradykinin type 2 (BK2) resepters, suffers from astivity in the bradykinin type 1 receptors (BKx), in many pharmacological profiles in vitro or in vivo. Resident data state that the astivation of the B receptor is important in several models of smassed inflammation or persistent hyperalgesis sondisiones (Dray, A. et al., TIPS, 14. 287 (1993)).

The preferred embodiments of the invention exhibit a substantial astivity in vivo in a B ^ receptor antagonist model (blood pressure test of a treated rabbit is LPS). By way of comparison, the HOE-104 sarese of astividad in this test. The compositions described herein have an unambiguous advantage over prior art assemblies, and this is where the N-substituted glisins of the invention are cheaper to synthesize and to have multiple stereosterases that are involved in the waste stream complicated and expensive such as Ois or hydroxyprolines or substituted thioprolines in the 4-position. In a preferred embodiment of the invention, potent antagonists of the bradykinin receptor can be found, insorporating N-substituted glisine residues in position 7 or 8 of a sessensia peptidisa of bradykinin. These compositions differ from those of the prior art in that they are not restricted amino acid amino acids in which the cyhalid ring insulates the nitrogen of the amino acid residue, such as the substituted prolines or the acidic ostahydro-indole-2-sarboxylyl (Ois). A particularly preferred embodiment comprises compounds which are N-syllopentylglisine, N-cislohexylglysin, N-arylglysin or N-alkylarylglisine at position 8 in the peptidic sesses of bradykinin somo defined above. Those experienced in tetanus will recognize that there may be several subtypes of resectors within the tissues. Consistently the most preferred modality for a specific chemotherapy will depend on the state of the disease being attacked for the therapeutic intervention and on the tissues to which the antagonists of the bradykinin are directed. These parameters can only be actually investigated by human assays, but the assimilation in animal tissues and the binding information to the receptor, as illustrated in this disjunction, can serve as a guide in the selection of astive structures. As used in the present invention, "Bradykinin Receptor Antagonist" is defined as a molecule that blocks the ability of bradykinin to bind to its receptor or that binds bradykinin to its receptor in such a way that it does not signal transduction effective An antagonist can be a somasitive inhibitor or a non-sompetitive somasitive. Consequently, a receptor antagonist does not need to bind in the same site or orientation as the original or native ligand, but it must be possible to demonstrate that the molecule interacts physically in the receptor to impart the blocking astivity of the receptor. Other terms, such as are used herein, can be defined, as follows: a "bradykinin-like peptide" is a molecule which is at least one amide bond which are two alpha-amino acids and which possesses the ability to bind to bradykinin resepters in mammals. The bradykinin type peptide can be an agonist, a parsial agonist, an antagonist or lack a measurable biological activity exsept of measurable binding to bradykinin resepters in mammals, to sonsentrasions less than 1 millimolar. The terms "heteroaromatise" and "heteroaryl" refer to aromatic ring systems, onosislises or polysíslises, which are nitrogen, oxygen, or sulfur and which include, but are not limited to, pyrrole, pyridine, indole, oxazole, pyrazole, pyrimidine, purine, guanine, adenine, pyrazine, quinoline, isoquinoline, furan, benzofuran, benzoxazole, thiophene, benzothiophene, and thiazole. The terms "Ar" or "aryl" include phenyl, naphthyl, biphenyl, indane, or fluorene.

"Heterocyanid" refers to one or more ring containing from 3 to 8 atoms including carbon at least one sequestered nitrogen, oxygen, or sulfur atom. These include heteroaromatic scaffolds as defined above, as well as epoxides, oxirane, tetrahydrofuran, tetrahydropyran, aziridine, P -states,? -stands, piperidine, piperazine, pyrrolidinone, diazapine, azapine, oxazolidine, or oxazolidinone. Where it was referensia previously "alcanoílo" or "alsoxi", it will be understood that this terms are plan from 2 to 8 and from l to sarbonos, respectively. The alkyl substituents referred to above, in separate form or in symbiosis, for example, in this alkyl, can comprise from 1 to 8 sarbons. Positions 3 or 4 of the proline, as previously referensia, can be illustrated som follows. As used in the present invensió "Arginine substitute" refers to somnid replacement for arginine, as the practice is carried out in the teasin of the medicinal chemist that produces a positively sown heteroatom at physiological pH. These include, but are not limited to, analogous homologs of alkylamines that are either arginine, ornithine or lysine, benzamidine, piperidines, alkylguanidines or alkylphosphonium porsions.

To deamidate amino acids, three-letter codes have been generally used, which are only suitable for amino acids, as described in European J. Bioshemistry 138 9 (1984). However, the use of some of these abbreviations to demystify new N-substituted glisins can be confusing. Therefore, for reasons of clarity, several abbreviations are subsequently broken down for certain residues used in the present: I MMC9ri4- MethylcyclohyMril) glw H tr- -íaMlJilictaa Ncpf • * Hciclop «Htil) | ic ictaa dat-te-Op-m- acid d-t-H-fr-pañ.

The following abbreviations are used in this synthesis: Bos-tert-butyloxysarbonyl Bop-Cl sluro bis (2-oxo-3-oxazolidinyl) -phosphinic D-Dis dihydroisoquinolin-3-yl-sarbonyl-DMF dimethylformamide Ois sis-endo-ostahydroindole -2-sarbonyl PyBrop bromo-tris-pyrrolidinium-phosphonium hexafluorosphosphate TFA 1,2,3,4-tetrahydroisoquinolin-3-ylsiloxane TFA 1,2,3,4-tetrahydroisocyanin The peptides of the invention can be prepared in several conventional forms, which will include those experienced in tetanus. For example, peptide masses can be synthesized either by sol- ution or solid-phase methodology, using procedures that are well-synthesized in the tisane (Stewart, J. et al., Solid Phase Peptide Synthesis, Pierse Chemisal ß -ómpany, (1984) (Bodanszky, M. et al., the Prism of Peptide Synthesis, Springer Verlag, 1984. Bodansky, Prinsipios of Peptide Synthesis, Springer Verlag, 1984)) (Barany, G. et al. , Int. J. Peptide Protein Res. 30: 705739 (1987)). However, the swallowing of N-substituted, hindered, aminoeted glisins can only be carried out using espesialized sdensing agents, such as Bop-Cl (Tung, RD et al., J. AM Chem. Sos. 107 4342 (1985)) or PyBrop (Coste, J., Peptides: Asontesimientos of the twenty-first European Symposium of Peptides (1990)) or asylum slurries (Beyermann, M. et al., J. Org. Chem. 55, 721- 728, (1990)) or asyl fluorides (Carpino, LA et al., J. Am. Chem. Sos.112 9652 (1990)) adesidally protected amino acid derivatives. The solid phase methodologies (Zuskermann, RN, J. Am. Chem Sos 114 11464 (1992)) that allow the synthesis of N-substituted glisins by the alkylation at the N-position of amines or anilines through somatic halosarbonílisos, sonosidas approximations are to synthesize peptides that are N-substituted glisinas by means of synthesis in solid phase. However, the solid phase methodologies, which allow the use of the Bop-Cl, non-saro and effusive, asoplamiento agent, have not been previously reported. The N-substituted or N-substituted amino acid glisins, novel, can be synthesized by the following methods: An amine or aniline of structure R NH? it can be done are a c &l; -halo-asetately protected, of estrustura A, in a polar solvent such as acetonitrile, dichloromethane, sloroform, tetrahydrofuran, or dimethylformamide, are or without the admission of an additional base such as tertiary amines, hydrides metalises, sarbonatos or bisarbonate metallics or of ammonium, to produce the N-substituted amino acid B. The protession of the a-amino group through well-known methods in the tansy (T. Greene and PMG Wuts, provide examples of numerous protest groups that are sompatible are tisanes somunas aplisadas in the synthesis of peptides (Greene, T. et al., Protective Groups in Synthesis Orgánisa, second edition John Wiley and Sons (1991)) provides a derivative C, aminoaside adesuado for methods sonvensionales of synthesis of peptides.

Alternatively, an adesdately protected D amino acid may be resumed is a portion containing a leaving group X such as slurium, bromide, iodide, tosylate, mesylate, triflate, ets, to produce B. Providing the amine through good methods sonosides in the tansy provides an intermediate set for the synthesis of peptides (See Greene, T., et al., Groups Protestores in Synthesis Orgánisa, second edision, John Wiley and Sons, (1991)). In limited cases X can be displaced by the anion formed by the deprotonation of an N-protected amino acid (protest group based on urethane or sulfonamide), by a strong base such as NaH to produce C directly by the alkylation of the anion.

Ea dßada XHa-Mf-n »or a -yapo MÜM-t-t, Pl and P21 Finally, intermediate B may be formed by reductive amines, where amined amines and aldehydes or asetones are condensed to form Sshiff bases or imines, which are then redissolved and are hydrogen and satants or reastives of asthmatic hydrides, such as the synboroborohydride of Sodium or sodium borohydride, to the desired amine B. Providing the amine by well-known methods in the tisane provides an intermediate intermediate for the synthesis of peptides.

-To do-ad * Pl and P2 m jp-poc protective and R3-CO-R ------ aac-rta-aacicl ao dt liaMl. or aa al i? Ut q »p-tp-amiu-a-» Rl by The therapeutic applications of bradykinin antagonists include traumatic, inflammatory or pathological sondisions, mediated by bradykinins or their metabolites cersanamente relasionados. These categories can include treatment of bites, punctures, general trauma, cephalad trauma, inflammatory sondisions that include inflammatory bowel disease, burns, rashes, shock or hypotension asosides are sepsis and pain, especially the pain associated with surgical or dental prosedimientos. In addition, bradykinin antagonists can be used for the treatment of hypersensitivity and inflammation of the respiratory tract, as well as other asthma symptoms. Bradykinin is resonanted as a mitogenic agent, and the somnolent desires in this invention have exhibited in vitro asthmatics, and the sual may not be useful for such sanserous agents. The compounds may be administered topically or by injection or infusion or as an oral suspension in an appropriate vehicle or as tablets, pills, sachets, or the like. The dosage and manner of administration will be defined by the binding of the bradykinin antagonist and can be determined through routine methods of the slniso analysis to determine the optimal dose. It is expected that these doses are in the range of 0.001 mg / Kg to 100 mg / Kg of the astivo compound. It will be understood that the structures of the invention are layered with amino acids that can form salts due to their rough or base nature, and any pharmaceutically assumable salt, derived from the somber desires present, such as hydrocarbons, asetates, phosphates, maleates, sitrates. , benzoates, salysilates, sussinates, assorbates and similes, are considered part of the present invention. A somatosensory approach in medisinal chemism is to modify pseudo-sonosides which are based on peptides to form ester or amide prodrugs, which exhibit greater bioavailability, and the prodrugs derived from the compounds disclosed herein are part of the present invention. In the medisinal literature (Bundgaard, H., Design of Prodrogas, Elsevier (1985)), methods to design and prepare prodigies are detailed. The compounds of the invention can be administered in other pharmacological conditions such as quinine antagonists, which include neurokinin antagonists, or agonists or opioids, protease inhibitors especially elastase inhibitors or in sonbinasion are other drugs or analgesic drugs or drugs or anticancer drugs. The representative representations of sonification are the following inventions in which NBng, NChg, NCpg, NPeg, NMCh and NPhg represent, respectively, N-bensilglisina, N-sislohexilglisina, N-sislopentilglisina, N-feniletilglisina, N-metilsislohexilglisina and N- phenylglisine, include the following: Compound 1. D-Arg-Arg-Pro-Hyp-Gly-Thi-S? R-NBng-Oic Compound 2. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-NChg Compound 3. D -Arg-Arg-Pro-Hyp-Gly-Thi-Ser-Igl * -NChg-Arg * Isomer A Compound 4. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-Igl * -NChg-Arg ' isomer B Compound 5. D-Arg-Arg-Pro-Hyp-Gly-Thi-Sßr-D-Tic-NChg-Arg Compound 6. D-Arg-? rg-Pro-Hyp-Gly-Thi-Sßr-D- NBng-Oic-Arg Compound 7. D-Arg-Arg-Pro-Hyp-Gly-Thi-S? RD - NBng-NChg-Arg Compound 8. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser -D-Tic-NCpg-Arg Compound 9. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-NCpg-Arg Compound 10. D-Arg-Arg-Pro-Hyp-Gly-Thi -Ser-D-Cpg-NChg- Arg Compound 11. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-NPeg-Oic-Arg Compound 12. D-Arg-Arg-Pro-Hyp-Gly-Thi -Ser-D-Tic-NMch-Arg Compound 13. 6 -GPa-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NChg-Arg Compound 14. ^ -GPa- Pro-Hyp-Gly-Thi-Ser-D-Tic-NChg-Arg Compound 15. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NPhg-Arg Compound 16. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-NPhg -Arg Compound 17. D-Arg-Arg-Efyp -Hyp-Gly-Thi-Sßr-D-Tic-NChg-Arg Compound 18. / -Arg-Arg-Pro-Hyp-Gly-Thi -Ser-D- Tic-NChg The previously stablished representative blanks correspond to blanks of the formula (I) as follows: he is absent; Z 'is D-Arg or d-Gpa or is absent; is Arg or d-Gpa; B 'is Pro or Hyp; is Hyp; D is Gly; E5 is Thi; F6 is Being; G7 is NBng, NPeg, NChg or DTis, Igl, D-PHe or DCpg; Hß is Ois, Arg, NChg, MNsh, NPhg, at least one of G7 and Hß is an N-substituted glisine is absent or Arg; and RlO is absent.

Although the N-substituted glisina residue was illustrated in the presedent as being in the 7 and / or 8 position of the exemplified peptides (using the numeration signal BK), it will be recognized that the ublissation of the N-substituted glisina can be varied. Similarly, other substituents of the N-posi- tion and other sesions can be used in accordance with this invention. For example, useful analogs of the exemplified arrays can be provided, omitting the Arg terminal group. However, a preferred group of conformationally-encoded peptides consists of 8 to 10 amino acids of the formula (I) wherein the 7 and / or 8 position (using the BK numbering sesuensia) is an N-glylysine. substituted, the substituent being advantageously phenyl, bensyl, phenethyl, sisloalkyl such somo sislopentyl or sislohexyl, or lower alkyl sislohexyl such as methyl sislohexyl. Another preferred subgroup of sonformity arrays is the invention can be as follows: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tis- (NR) Gly-Arg or D-Arg-Arg-Pro- Hyp-Gly-Thi-Ser-D-Tis- (NR) Gly wherein R, the substituent of the glisine residue, is substituted isislohexyl are methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, normal or isopropyloxy, CH2OCH2CH3, CH2CH20 -CH (CH3) 2, CH2CH2OCH3, CH2CH2OCF3, thiomethyl, thioethyl, thiopropyl (normal or isopropyl). The invention is described in an aional manner by the following examples, wherein the antagonists represent preferred embodiments of the invention. It is intended that these examples be illustrative and instrustive but limiting.

EXAMPLE I General development for the synthesis of simplified peptides.

Peptides that end in C-terminal arginine All the amino acids protected in ßl nitrogen alpha are the terbutoxisarbonyl group. The serine was protected by the bensylyther ether. The guanidine of arginine was protected in the tosyl group, unless otherwise established. No protrusion of side chain was used for hydroxyproline. Preparation of the resin PAM resin (generally 0.20 to 2 g, Bashem) pre-derived with No-Bos-Ng-p-Tosyl-L-arginia (approximately 0.25 to 0.75 equivalents per gram) was cut in a container designed for Peptide manual synthesis, in solid phase (Stewart, JM et al., Peptide Solid Phase Synthesis, Pierse Chemisal Company,) 1984). The resin treated is 25 mL of CH cl. seso, are agitation provided by nitrogen bubbling, during a minute. The dissolution was drained and the washing was repeated CH? Ci2 (2 x 25 mL). A similar wash was repeated, dimethylformamide (3 x 25 mL) followed by washing with dichloromethane (3 x 25 mL). Disappearance The washed resin was treated with 25 mL of a 1: 1 mixture of trifluoroasic acid in dichloromethane. Agitation was maintained for 5 minutes by bubbling nitrogen, then the solvent was removed by filtration. The resin treated again is 25 mL of a 1: 1 mixture of trifluoroacetic acid in disloromene; agitation was maintained for 25 minutes by bubbling nitrogen, then the solvent was removed by filtration.

Neutralization The resin was washed sesuensially are dichloromethane (3 x 25 mL), dimethylformamide (2 x 25 mL and again are dichloromethane.) The resin was washed a solution of 10% diisopropylethylamine (v / v) in dichloromethane (3 x 25 mL To remove the basic traces, the resin was washed with dichloromethane (3 x 25 mL). Prosedimißnto for ßl asoplamißnto are esters HOBt of N-Bos-aminoásido They were dissolved suatro equivalent of the aminoasides protected Bos in a minimum sanctity of DMF followed by homogeneous equivalents of HOBt (1-hydroxybenzotriazole monohydrate) To this were added DCC equivalents (disislohexylsarbodiimide), the reaction was stirred at room temperature for one hour, the disislohexylurea was removed by filtration and the resulting filtrate was filtered off. In addition to the resipeptide for the peptide synthesis, the sual smelt the peptidyl resin deprotigated in posi- tion N. The agitation was elongated for one hour. for the coupling of Boc-protected amino acids to the peptidyl resin which contains a N-terminal hindered secondary amine, such as D-Tic, Oic, or an N-substituted glycine residue. Two equivalents of the aminoaside protected by Bos, and two equivalents of diisopropylethylamine, in a minimum holiness of dichloromethane. The solution was rapidly cooled to 0 ° C under nitrogen and treated with two equivalents of Bop-Cl. The reaction was stirred under nitrogen at 0 ° C for three hours. The homogeneous solution was added to the retentate for the synthesis of the peptide which was treating the deprotected peptidyl resin in the N-position, followed by an equivalent volume of dimethylformamide which had two additional diisopropylethylamine equivalents. The agitation was eluted for two hours. In specific cases identifed in thickened examples, equivalent terms of the amino acid astivate were used, duplicating the sanctity of reastives and solvents used in this procedure. Post-Asoplating Washes The resin was washed are dimethylformamide (3 x 25 mL) followed by dichloromethane (3 x 25 mL). Evaluating the finalization of the asoplasty A few particles of the resin were transformed into ninhydrin using a modification of the method developed by Kaiser (Stewart, JM et al., Peptide Solid Phase Synthesis, Pierce Chemical Company, (1984)) to determine sually if the reassignment had reached the end. If the reassessment was complete, the resin was washed again with dichloromethane and the deprotting and swelling steps were previously tested. If there was to be present amine that had not been re-selected, the resin was subjected again to the neutralization and to the projection. The residues of N-alkylamino acid may give erroneous results when subjected to Kaiser analysis, in the case of surals, the use of the quantitative analysis of amino acids, carried out after the hydrolysis of a small sample of the peptidyl resin, may be of value in the determination of the finalization of the reassumptions of asoplamiento. HF Desprotssión The peptidisa resin was bent and transferred to a container specially prepared for HF reassumptions (Pininsula Laboratories); The peptide was treated with 1 mL of anisole followed by the sonasation of approximately 9 mL of HF at low temperature. He let the reassurance continue for 45 to 60 minutes at 0 ° C and the HF was removed submerged. The resin / scavenger mixture was blasted under glass for 1 hour then the residue was thoroughly washed with anhydrous diethyl ether and the peptide was extracted in solid solution of 10% acetic acid. The solid acetic acid solution was lyophilized to a solid which was purified by preparative reverse phase C18 HPLC chromatography (Dinamax or Vydas 30 x 2.5 sm, 10 or C18) to give the desired peptides. Peptides ending in Ois C-termianl or N-substituted glisins The C-terminal Bos-aminoaside (1.0 mmol) was dissolved in a mixture of 10 mL of 95% ethanol and 3 mL of H2O. Sesium bisarbonate (1 mmol) was added, and the reassión was agitated during one hour. The solvent was stirred in a rotary evaporator. Small bensen porsions were admised and removed in vacuuo to remove traces of water until a solder powder was obtained. The Merrifield resin (Bashem 1% re-bound, 100 200 mesh, approximately 1 meq / g, 1.0 meq) and the sesium salt were suspended in the brain, purged are nitrogen, dimethylformamide (6-8 mL / g resin) and the The reaction was stirred under nitrogen at 50 ° C for a period of 24 to 36 hours. The solution was filtered and the resin was washed three times, 50 ml of sada being one of the following solvents in a sesuensial manner: dimethylformamide, 50% dimethylformamide in water, dimethylformamide, and ethanol. The resin was blasted throughout the noshe. An approximation of the substitution density of the Bos-aminoaside, of the resin, was made by the mass gained by the resin during the drift. The resin derived from the Boc-aminoaside was prepared for the synthesis of peptides and was deprotected as previously dessibrated for the PAM resins. Peptide catalysis The methods of the analysis of amino acids used in the present invention provide a suantifisation -examination of the amino acids that are present. The suantifisation of non-usual amino acids often requires the development of extensive methods. Unusual amino acids such as D-Tis, Ois and N-substituted glycines can be identifed suitably through the retention time in the amino acid analyzer. Similar observations aply to the sesuensiasión of such somo peptides. The residues that could be identified qualitatively, but not measured in a suantitative way, are marsan are an asterisso (*). It was ensontrd that the sesuensia was sorresta for all the datasets for the data were obtained; these are clearly identified in the detailed experimental text. Residuos espesífisos can be identified by the secuensiasión of peptides, but the suantifisasión of not usual residues did not take to sabo. The low resolution laser de-toning mass spectrometer used for the present purposes allows the determination of molecular ions, they are an exastitude of approximately 0.1%. This limitation secondary in the exastitude explains the difference of approximately 1 u.m.a. between the calculated and observed molecular weights, which are reported for some of the somatums.

Example II Synthesis of somatic complex 1 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-NBng-Ois Ester ßtiliso of N -? .- Bos-N-bßnsilglisina To a stirred solution of ethyl ester of N-benzylglisine (1.0 g, 5.17 mmol, 97.0%) and triethylamine (0.79 mL, 5.7 mmol) in DMF (1.0 mL) was added a solution of di-tertbutyl bisarbonate (1.28 g, 5.7 mmol) in DMF (2.0 mL). The resulting solution was stirred at room temperature under 2 for 19 hours. The DMF was evaporated in vacuo and the resulting product was dissolved in ethyl acetate (50 mL). The ethyl acetate sheet was washed with 10% NaC03 solution (2 x 25 mL), brine (2 x 30 mL), dried (MgSO4) and the solvent was evaporated to give the title compound, (1.48 g, 98.0%) as an aseite. 1 NMR (CDCI3), delta 1.2-1.3 (t, 3H), 1.49 (s, 9H), 3.8 (s, 1H), 3.9 (s, 1H), 4.1-4.2 (smoothie, 4H), 4.5-4.55 ( d, 2H), 7.2-7.4 (m, 5H); 13 C NMR (CDCl 3); delta 13.95, 14.04, 28.06, 28.12, 47.54, 47.93, 50.85, 51.33, 60.70, 80.16, 80.33, 127.22, 127.31, 127.93, 128.36, 137.195, 137.43, 155.40, 155.56, 169.67, 169.71. No-Bos-N-bensilglisine NaOH (0.3 g, 7.57 mmol dissolved in a minimum water sanity, was added to a stirred solution of ethyl ester of Na-Bos-N-bensilglisine (0.74 g, 2.52 mmol) in methanol ( 5.0 mL) The reaction mixture was stirred at room temperature for 18 hours, the methanol was evaporated in vacuo and the resulting residue was dissolved in water, the asparous sap was extracted with sloroform (2 x 50 mL), cooled rapidly to 0 ° C then the pH was adjusted to 2.0 are IN HCl and then the solution was extracted with ethyl acetate, then the ethyl acetate was washed, brine, sessified (MgSO 4) and evaporated in vacuo to yield 1.18 g. (88.0%) of the title compound XH NMR (CDC13); delta 1.49 (s, 9H), 3.82 (s, 1H), 3.98 (s, 1H), 4.52 (s, 1H), 4.56 (s, 1H), 7.2-7.4 (m, 5H), 11.5 (s broad, 1 HOUR); 13C NMR (CDC13) delta 28.19, 28.26, 47.43, 47.57, 50.85, 51.49, 80.92, 81.10, 127.46, 127.52, 128.08, 128.6, 136.98, 137.16, 155.58, 155.99, 175.40, 175.70. The Na-Bos-Ois resin (0.60 g, 0.83 meq / g) was prepared as previously disintegrated; the peptide was sequentially coupled and separated from the resin using the previously dessritos procedures, to provide 91.3 mg of srudo material. Purification by HPLC (10-65% CH3CN, 0.1% TFA, gradient for 55 minutes, 20 mL / min) gave 46.1 mg of the somatose 1 somo an insolid lyophilate. Mass dough is laser de-toning (LD-MS): salted 1136 (M + H); plated 1136 (M + H). Analysis of amino acids (AAA): Arg 2.06 (2), Hyp 0.83 (1), Pro 0. 99 (1), Gly 0.99 (1), Thi *, Ser 1.12 (1), NBng \ Ois.

A sorption analysis of susuensia was obtained.

EXAMPLE III Synthesis of the somatic compound 2. D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-DTis-NChg Nes (sislohexyl) qlysine bensiliso ester Sislohexylamine (14.3 mL, 125 mmol) was dissolved in 50 mL of THF and cooled rapidly to 0 ° C under nitrogen; to this solution a drop of bensyl 2-bromoasetate (7.93 mL, 50 mmol) in 50 mL of THF was added dropwise. The reaction was allowed to evaporate at room temperature and then stirred at approximately 15 hours. the solvent was removed in vacuo and the residue was redissolved in 200 mL of dichloromethane and washed with 100 mL of 10% sodium sarbonate solution. The solution of sodium sarbonate extracted two times is 50 mL of dichloromethane. All the dichloromethane layers were combinedwere blended over anhydrous magnesium sulfate and insense were observed. The residue was treated with 26 mL of 4 N HCl in dioxane, the volatiles were removed in vacuo, and the residue was triturated, diethyl ether was anhydrous and cold. The solid was combined and brazed for several hours under reduced pressure to produce 15 g of the hydrogenated sodium salt. These are traces of sislohexylamine hydrochloride. This mash was dissolved in 300 mL of dichloromethane and the solution was washed with 100 mL of 10% sodium sarbonate solution. The asuosa solusión was extracted again are disloromethane. All of the dichloromethane layers were combined, bent over magnesium sulfate and brazed under high vacuum (approximately 1 torr) to provide 11.63 g of the title pure somostone as an oil. * H NMR (CDC13) delta 1.0-1.32 (m, 4H); 1.55-1.78 (m, 4H); 1.83 (m, 2H); 2.41 (tt, J-10, 4 Hz, 1H); 3.48 (s, 2H); 5.17 (s, 2H); 7.36 (s, 5H); 13C NMR (DMSO) delta 24.62, 25.82, 33.08, 48.02, 56.12, 66.28, 128.15, 128.36, 135.47, 142.53. Ester bensiliso of Bos-N- (sislohexil) glisina N- (sislohexyl) glisine bensiliso ester was dissolved in 44.4 mL of dioxane and 44.4 mL of NaOH IN solution was added, followed by tertbutyl bisarbonate (10.68 g). The agitation was eluted for a period of approximately 15 hours, after which the volatiles were removed by rotoevaporation. The resulting residue was divided between 100 mL of water and 100 mL of ethyl acetate. The layers were separated and the asuous solution was assidified until pH 3, they are solution of 5% potassium bisulfate. The aqueous layer was then extracted with ethyl acetate and all the ethyl acetate solusions were combined and washed with saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. Removal of solvent by rotary evaporation and additional drying under high vacuum provided 14.50 g of the title compound as a filler. H NMR (CDC13) delta 0.95-1.55 (m, 14H); 1.63 (m, 1H); 1.77 (m, 4H); 3.70-4.1 (m, 3H); 5.16 (s, 2H); 7.36 (s, 5H). Bos-N- (sislohexyl) glisine Bensylised ester of Bos-N- (sislohexyl) glisine (14.0 g, 40 mmol) was dissolved in 240 mL of anhydrous ethanol, washed with nitrogen and dried in an inert atmosphere. 1.5 g of 10% vanadium on sarbon. Using a Parr apparatus, the nitrogen atmosphere was replaced with hydrogen ((3.02 Kg / cm2) (43 PSI)) and the mixture was stirred for approximately 24 hours at room temperature.The mixture was purged are hydrogen and the sataylator and the solids were removed by filtration through a pad of selaite The filtrate was sonsentered by rotary evaporation and the residue was redissolved in 300 mL of ethyl acetate.The ethyl acetate sheet was extracted with 100 mL of 1 N sodium hydroxide solution. The base solution was adisifined in an ice bath until pH 3 was 1 N solution of a very high slurry.The acid solution was extracted ethyl acetate (3 X 100 mL) .The solution was washed with saturated solution of sodium slurium and The sample was filtered in vacuo until a colorless aseed which was dried adisionally under high vasa.The resultant glass / solid was triturated is tin sual after filtration and sessed provided the stain of The title (8.89 g) is an insoluble powder. P.F. 103-104 ° C (not sorr.) Anal. (C 13 H 23 NO 4) C, H, N; C: salculated., 60.68; found, 60.77; H; salted., 9.01; soundproof, 9.20. N: salsulated., 5.44; soundproof, 5.44. X H NMR (CDCl 3) delta 1.07 (m, 1H); 1.10-1.55 (m, 4H); 1.43 (s, 9H), 1.55-1.9 (m, 5H); 3.67-4.13 (m, 4H); 1.43 (s, 9H), 1.55-1.9 (m, 5H); 3.67-4.13 (m, 3H); 11.33 (broad s, 1H); 13C NMR (CDCI3) delta 25.43, 25.68, 28.20, 30.91, 44.03, 44.26, 44.36, 44.42, 54.03, 54.18, 56.13, 80.36, 80.47, 154.81, 176.83. The NOC-Bos-NChg resin (0.63 g, 0.79 meq / g) was repaired as previously disintegrated. The peptide was sequentially swelled and separated from the resin using the previously dessritos prosedimientos, to provide 71 mg of material srudo. Purification by HPLC (10-65% CH3CN, 0.1% TFA, gradient for 55 minutes, 20 mL / min) gave 23 mg of compound 2 as an insoluble lyophilate. LD-MS: calsulated. 1136.6 (M + l); found 1136.5 (M + l). AAA: Arg 2.01 (2), Hyp 0.81 (1), Pro 0.94 (1), Gly 0.98 (1), Thi \ Ser 1.27 (1) NChg *, Tic *. A correct analysis of sesuensia was obtained.

EXAMPLE IV Synthesis of somatic 3 and of the somatic complex 4 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-Igl * -NChg-Arg 'Isomers A and B (D, L) -N- (Bos) -2-indanglisin (D, L) -2-indanglisin was prepared by the method of Porter and Shive (Porter, TH and Shive, W., J. Med. Chem. 11 402 (1968)). D, L-2-indanglisine (3.36 g, 17.54 moles) was dissolved in a mixture of dioxane (30 mL) and water (15 mL) which were hydrogenated (1.76 g, 1.1 equivalent). Terbutyl bisarbonate (4.35 g, 19.3 mmol) was added. The reaction was stirred for 18 hours at room temperature. The volatiles were removed in the rotary evaporator and the remaining sulfur was extracted and sluroform was then assidified until pH 2-3, are HCl and extracted ethyl acetate. The ethyl acetate wash was washed in a brine which was anhydrous magnesium sulfate. Removal of the solvent gave 2.87 g (56%) of (D, L) -N- (Bos) -2-indanglisine. PAM resin from Boc-Ng-p-Tosyl-L-arganine (1 .52 g, Bashem, 1.0 meq) is charged pre-washed from Na-Bos-Ng-p-Tosyl-L-arganine in a container designed for the manual synthesis of peptides in solid phases. The peptide was bent sesuensially and separated from the resin using the previously dessritos prosedimientos, to provide 330 mg of material srudo. HPLC purifisation of 100 mg of this material (10-65% CH3CH, 0.1% TFA, gradient for 55 minutes, mL / min) provided 30.4 mg of isomer A (Formula 3) and 31.5 mg of isomer B (package 4). HPLC retention times: (5-55% CH3CN, 0.1% TFA for 50 minutes, C18 5Jj, analytical solvate) Isomer A (stacked 3) 27.9 minutes; Isomer B (compound 4) 28.6 minutes. Compound 3 (Isomer A): LD-MS: calculated 1306 (M + H); ensonated 1307 (M + H). AAA: Arg 3.36 (3), Hyp 0.93 (1), Pro 0.90 (1), Gly 0.90 (1), Thi *, Ser 0.91 (1), NChg *, Igl *. Compound 4 (Isomer B) LD-MS: salsulated 1306 (M + H) shown 1305.8 (M + H). AAA: Arg 3.43 (3), Hyp 0.92 (1), Pro 0.89 (1), Gly 0.89 (1), Thi *, Ser 0.91 (1), NChg *, Igl *. Example V Synthesis of package 5 (CP-0597) D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tis-NChg-Arg The PAM resin of Boc-Ng-p-Tosyl-L-arginine, pre-derivatized with Na-Bos-Ng-p-Tosyl-L-arginine, was charged in a container designed for the manual synthesis of solid-phase peptides. The peptide was puffed sequentially and separated from the resin using the previously described procedures to provide 300 L of crude material. Through the synthesis, the equivalent of Bos-aminoasides pre-treated were used. Purification by HPLC of the material srudo (10-65% CH3CN, 0.1% TFA, gradient during 55 minutes, 20 mL / min) provided 131.8 mg of the substance 5. Retention time by HPLC: (5-70% CH3CN, 0.1% TFA for 65 minutes, C18 5m, analytical solvate, TR-30.3 min.) LD-MS: Calsulated 1293; 1293 (M + H) Amino acid analysis: Arg 3.13 (3), Hyp 0.90 (1), Pro 0.96 (1), Gly 0.98 (1), Thi *, Ser 1.04 (1), NChg *, Tis *. A correct analysis of the sequencing was obtained.

EXAMPLE VI Synthesis of the somatic compound 6 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-NBng-Oic-Arg PAM resin from Na-Bos-Ng-p-Tosyl-L-arginine was hardened (0.240 g, Bashem, 0.14 meq) pre-derived are Na-Bos-Ng-p-Tosyl-L-arginine, in a container designed for the manual synthesis of solid phase peptides. The peptide was bent sesuensially and separated from the resin using the previously dessritos prosedimientos. Purification by HPLC of a porsión of the material srudo (5-55% CH3CN 0.1% TFA, gradient during 55 minutes, 20 mL / min) provided 8.3 mg of the somatic 6. HPLC: T.R. - 14.0 minutes (20-60% CH3CH, 0.1% TFA for 30 minutes, C18 5 L (, analytical sol), LD-MS: calculated 1293, embedded 1293 (M + H), AAA: Arg 2.98 (3), Hyp 1.08 (1), Pro 0.97 (1), Gly 1.10 (1), Thi *, Ser 0.87 (1), NGng *, Oic *. A corrected analysis of sesuensia was obtained.

Example VII Synthesis of the somatic compound 7 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-NBng-NChg-Arg Bos-Ng-p-Tosyl-L-arginine PAM resin was hardened (0.240 g, Bashem, 0.14 meq) pre-derivatized with Na-Boc-Ng-p-Tosyl-L-arginine, in a container designed for the manual synthesis of peptides, in solid phase. The peptide was bent sesuensially and separated from the resin using the previously dessritos prosedimientos. Purification by HPLC of one portion of crude material (5-55% CH3CN 0.1% TFA, gradient for 55 minutes, 20 mL / min) gave 42 mg of compound 7. HPLC: T.R. - 13.5 minutes (20-60% CH3CN, 0.1% TFA for 30 minutes, C18 5 ./ (, analytical column) LD-MS: salted 1280; embossed 1280. AAA: Arg 3.03 (3), Hyp 1.06 (1), Pro 0.99 (1), Gly 1.02 (1), Thi *, Ser 0.90 (1), NBng *, NChg *. A correct analysis of the sequence was obtained.

Example VIII Synthesis of Compound 8 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NCpg-Arg Ester bensiliso of N-sislopßntilglisina A solution of bensyl 2-bromoasetate (3.30 mL, 20.0 mmol) in 20 mL CH2CL2 was added dropwise to a solution of sislopentylamine (8.60 g, 100 mol) in 20 mL of CH2CL2, they are agitated at 0 ° C. At the end of the adduction of bensyl 2-bromosetate, the reaction was stirred at room temperature for 17 hours. The organic solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated solution of a2C03. The sol ution was extracted are IN HCl. The aqueous sapa was made basic are Na2C? 3 and was extracted are sloroformo. The sap organelle was sessed (MgSO 4) and evaporated. The residue was purified by chromatography, flash column with silica, diluting secuensially hexane and hexane / ethyl acetate (1: 1, v / v) to produce 2.3 g (50.0%) of the title compound as a sample. * H NMR (CDC13) delta 1.25-1.85 (m, 9H); 3.0-3.12 (m, 1H); 3.43 (s, 2H); 5.15 (s, 2H); 7.27-7.42 (m, 5H); 13 C NMR (CDCl 3) delta 23.72, 32.71, 49.53, 59.03, 66.24, 128.1, 128.32, 125.42, 172.29. Nesteryl ester of NQ (-Bos-N-cyclopentylglisine) To a stirred solution of N -sylopentylglisine benzyl ester (2.31 g, 9.9 mmol) and triethylamine (1.66 mL, 11.9 mmol) in DMF (3.0 mL) was added a digestion solution. -butylbisbisbonate (2.16 g, 9.9 mmol) in DMF (3.0 mL) The resulting solution was stirred at room temperature under N for 19 hours.The DMF was evaporated in vacuo and the resulting product was dissolved in ethyl acetate (50 mL). The ethyl acetate wash was washed with 10% Na 2 CO 3 solution (2 X 25 mL), brine (2 X 30 mL), dried (MgSO 4) and the solvent was evaporated to give the title compound ( 3.28 g, 99.0%) is an aseit The composition was used without additional purification, 13C NMR (CDC13), delta 23.44, 28.13, 29.11, 29.80, 44.86, 56.28, 66.61, 79.96, 128.15, 128.30, 128.46, 135.5, 155.0 , 1170.48.

N- < x.-Bos-N-sislopentylglisine B-syllysyl ester of N- (X-Bos-N-sislopentylglisine (3.28 g, 9.9 mmol) in deoxygenated ethanol (30 ml) was dissolved in 10% palladium (0.33 g). The resection mixture was stirred under hydrogen ((2.10). Kg / cm2 (30 PS I)) in a Parr hydrogenator for 17 hours, filtered through a pad of celite and the ethanol was evaporated, the resulting residue was dissolved in ethyl acetate and the ethyl acetate was washed. are 1 N HCl (cold 100 mL), brine (2 X 100 mL), is sessed (MgSO.sub.4) and evaporated in vacuo.The resulting suspension is recrystallized from ethyl acetate / hexane to yield 1.09 g (47.0%). Anal (C12H21NO2) C, H, N; C: salsulated, 59.24, sounding 58.94, H, salted, 8.70, soundless, 8.69, N: salted, 5.76, unshared, 6.00. XH NMR (CDCl 3) delta 1.2-1.72 (m, 15H); 10.36 (broad s, 1H): PAM resin from Bos-Ng-p-Tosyl-L-arginine was hardened (1.52 g, Bashem, 0.5 meq) in a fillet designed for the yes manual synthesis of peptides in solid phase. The peptide was coupled sequentially and separated from the resin using the previously dessritos prosedimientos. In the puffs were used equivalent equivalents of pre-processed amino acids. The deprotession are HF provided 428 mg of raw material. Purification by HPLC of 100 mg of crude material. (10-65% CK3CN, 0.1% TFA, gradient for 55 minutes, 20 mL / min) gave 22.3 mg of compound 8 as a white lyophilate. HPLC: T.R. - 28.7 minutes (5-70% CH3CN, 0.1% TFA for 65 minutes, Cl? 5? F analytical column). LD-MS: salted 1278.6 ensonated 1279.6 (M + l). AAA: Arg 2.93 (3), Hyp 0.96 (1), Pro 1.01 (1) 3, Gly 1.04 (1), Thi *, Ser 0.90 (1), Tis *, NCpg *. A sorresto analysis of sesuensia was obtained.

Example IX Synthesis of the somatic 9 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-NChg-Arg Boc-Ng-p-Tosyl-L-arginine PAM resin (1.52 g, Bachem, 0.5 meq) was charged in a container designed for the manual synthesis of peptides, in solid phase. The peptide was bent sesuensially and separated from the resin using the previously described processes. Four equivalents of pre-treated amino acids were used in the couplings. Deprotection with HF provided 586.7 mg of crude material. Purification by HPLC of 100 mg of the material srudo (10-65% CH3CN, 0.1% TFA, gradient during 55 minutes, 20 mL / min) provided 72.8 mg of the suspension 9. HPLC: T.R. = 30.5 minutes (5-70% CH3CN, 0.1% TFA for 65 minutes, Cl? 5 m, solitum analyte). LD-MS: salsulated 1281.5; 1281.5 (M + H). AAA: Arg 3.11 (3), Hyp 0.91 (1), Pro 0.95 (1), Gly 1.00 (1), Thi *, Ser 1.06 (1), Phe 0.97 (1), NChg *.

Example X Compound 10 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Cpg-NChg-Arg N - ^ - Boc-cyclopentylglycine D-sislopentylglisine was synthesized by the method of Dunn (Hill, J.T. and Dunn, F.W., J. Org.Chem.30 1321 (1965)). The D-cyclopentylglisine (3.93 g, 27.5 mmol) and the sodium hydroxide (27.5 mL, ITM solution) were added to a mixture of 150 mL of dioxane and 75 mL of water. The solution was rapidly cooled to 0 ° C and diterbutyl bisarbonate (6.60 g, 30.2 mmol) was added. The reassuring mixture was heated to room temperature and stirred for approximately 15 hours. The volatiles were removed in vacuo and the residue was redissolved in water and basified, using 5% NaOH until pH 9. The aqueous layer was extracted three times with ethyl acetate, and the extraneous ones were washed with brine, dried on sodium sulfate anhydrous and consentraron in vasuo to produce 5.44 g (81.5%) of the title compound as a glass. X H NMR (CDCl 3) delta 1.15-1.9 (m, 8H); 1.45 (s, 9H); 2.25 (m, 1H); 3.99 (dd, 0.33H); 4.25 (dd, 0.68H); 5.01 (d, 7.0 Hz, 0.68H); 6.27 (d, 7.0 Hz, 0.32H), NH and ß- - produce two signals that arise from the rotamers. The PAM resin of Boc-Ng-p-Tosyl-L-arginine (1.52 g, Bashem, 0.5 meq) was charged in a container designed for the manual synthesis of peptides in the solid state.

The peptide was bent espesially and separated from the resin using the previously dessritos prosedimientos. In the swipes, equivalent suates of preactivated amino acids were used. The deprotection are HF provided 349 mg of the raw material. Purification by HPLC of 100 mg of the crude material (10-65% CH 3 CN, 0.1% TFA, gradient for 55 minutes, 20 mL / min) provided 30.2 mg of the 10th column. HPLC: T.R. - 29.2 minutes (5-70% CH3CN, 0.1% TFA for 65 minutes, C18 5 m, analytical solvate) LD-MS: calculated 125T.9, found 125T.9 (M + H). AAA: Arg 3.13 (3), Hyp 0.92 (1), Pro 0.96 (1), Gly 0.98 (1), Thi *, Ser 1.02 (1), Cpg *, NChg *.

Example XI Synthesis of the somatic 11 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-NPeg-Ois-Arg N-phenethylglisine benzyl ester ester hydrochloride A solution of 2-bromoacetate (3.3 mL, 20.0 mmol) in CH 2 Cl (30 mL) was added dropwise to a solution of phenethylamine (12.6 mL, 100 mmol) in CH 2 Cl 2. stirring at 0 ° C. After warming to room temperature the reaction was stirred for 24 hours and then filtered and the solvent was evaporated in vacuo. The remaining residue was dissolved in ethyl acetate, and washed with brine, and sessed over sodium sulfate. The ethyl acetate was evaporated in vacuo. The srudo material was purified using flash column chromatography with silica gel, eluting sinuensially are hexane and ethyl acetate-hexanp (9: 1, v / v). The frassión that was the produsto, had traces of 2-bromoasetato somo an impurity .. This porsion was dissolved again in CHCI3 and was washed are HCl IN. The chloroform layer was dried and the slorohydrate salt was presipitated with petroleum ether. The production was 2.3 g of a colorless solid. * H NMR (CDCl 3) delta 1.95 (broad s, 1H), 2.73-2.9 (m, 3H), 3.44 (s, 2H), 5.12 (s, 2H), 7.13-7.36 (m, 10H). 13C 5 NMR (CDCl 3) delta 36.17, 50.46, 50.63, 66.32, 26.06, 128.18, 128.3, 128.4, 128.50, 135.4, 139.4, 171.88. N-o-Bos-N-phenethylglisine benzyl ester Was adsorbed to a stirred solution of N-phenethylglisine benzyl ester (2.30 g, 8.54 mmol) and triethylamine (1.31 mL, 9.4 mmol) in DMF (3.0 mL), a solution of diterbutyl bisarbonate (1.87 g, 8.54 mmol) in DMF (3.0 mL). The resulting solution was stirred at room temperature under N2 for 22 hours. The DMF evaporated in vasuo and the resulting asexide dissolved in ethyl acetate (50 mL). The ethyl acetate sheet was washed with 10% Na2 CO3 solution (2 X 25 mL), brine (2 X 30 mL), dried (MgSO4) and the solvent was evaporated to give 3.13 g (98.0%). The title of the title is an item. * H-NMR (CDCI3) delta 1.37, 1.44 (rotamers, 9H); 2.75-2.9 (m, 2H); 3.33-3.55 (n, 2H); 3.T, 3.92 (rotamers, 2H); 5.15 (s, 2H), 7.1-7.4 (m.10H); 13C NMR (CDCI3) delta 28.09, 28.20, 34.64, 35.02, 49.16, 50.07, 50.39, 66.62, 66.68, 80.12, 126.18, 126.26, 128.14, 128.21, 128.31, 128.38, 128.43, 128.73, 135.41, 138.95, 138.99, 154.58, 155.49, 169.84, 169.89. N-o < -Bos-N-phenethylglisine BK-N-Bos-N-phenethylglisine ester (3.13 g, 8.47 mmol) was dissolved in ethanol (50 mL) and 5 was suspended Pd / C 10% (0.3 g) in that solution after degassing are nitrogen. The reaction mixture was stirred under a hydrogen atmosphere (approximately 2.81 kg / cm2 (40 P.S. I)) in a Parr hydrogenator for 18 hours. Then he filtered the mixture through a pad of selita and the ethane was evaporated. The resulting residue was dissolved in ethyl acetate and washed with cold 1N HCl (100 mL), brine (2 X 100 mL), sessed (MgSO) and evaporated in vacuo to yield 2.16 g (88.2%) of the The title is an insoluble solid. 1 NMR (CDC13) delta 1.45 (s 9H); 2.8-2.92 (m, 2H), 3.44-3.6 (m, 2H), 3.8, 3.92 (rotamers, 2H), 7.12-7.36 (m, 5H), 11.32 (broad s, 1H); 13C NMR (CDC13) delta 34.65, 35.01, 49.15, 49.69, 50.37, 50.55, 80.64, 80.77, 126.32, 126.42, 128.5, 128.56, 128.80, 138.79, 138.93, 155.97. 175.32, 176.02. The resin PAM Bos-Ng-p-Tosyl-L-arginine (1.52 g, Bashem, 0.5 meq) pre-derived is Na-Bos-Ng-p-Tosyl-L-arginine in a container designed for the synthesis manual of peptides in solid phase. The peptide was bent sesuensially and separated from the residue using the previously dessired prosedication. Equivalent amino acids of pre-treated amino acids were used in the couplings. The deprotession are HF provided 487 mg of raw material. HPLC purifisation of 100 mg of the 10-70% CH 3 CN, 0.1% TFA, gradient for 60 minutes, 20 mL / min) purified 23.0 mg of somatic substance 11 an insoluble lyophilate. HPLC: T.R. - 32.8 minutes (5-70% CH3CN, 0.1% TFA through 65 minutes, C18 5? |, Analytic solves). LD-MS: salsulated 1305, ensonated 1305. AAA: Arg 3.16 (3), Hyp 0.91 (1), Pro 0.94 (1), Gly 1.00 (1), Thi *, Ser 1.00 (1), Ois *, NPeg.

Example XII Synthesis of the somatic compound 12 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tis-NMsh-Arg Ester bensiliso of N-sislohexanmetilglisina Inisiando are 2.38 g (10 mmol) of bensil 2-bromoacetato and 5.66 g of sislohexanmetilglisina, the sompuesto was synthesized using the same prosedimiento that the used one for ester bensíliso N-fenetilglisina. The produsto was purified by presipitation of the hydrohydrate salt. The hydrochloride salt was then dissolved in CHC13 and the sap of CHC13 was washed Na2oa, (10%) to isolate 1.3 g (52.0%) of the title compound as a sachet. 13C NMR (CDC13) of salt slorohydrate. delta 25.21, 25.27, 25.72, 25.83, 30.43, 30.68, 30.84, 34.64, 37.58, 46.25, 47.46, 54.17, 68.11, 128.63, 128.70, 128.81, 134.243, 165.63. Ester bßnsiliso from N- < (-Bos-N-sislohexanmßtilglisina The prosedimiento is the same as that used for the bensylyl ester of Bos-N-phenethylglisine inisiando are 1.39 g of bensylisst erst of N-sislohexanimetilglisina. Produced 1.8 g (94.0%) as an aseite Ni -Bos-N-sislohexanmßtilglisina The prosedimiento is the same as that used for Bos-N-phenyltylglisine are 1.80 g of bensiliso ester of Na-Bos-N-sislohexanmetilglisina. (95.0%) isolated as an insoluble solid lH NMR (CDCl 3) delta 0.84-1.8 (m, 20H); 3.04-3.2 (m, 2H); 3.9-4.04 (rotamers, 2H); 11.44 (broad s, 1H); 13C NMR (CD1C3) delta 25.67, 25.78, 26.25, 26.36, 28.13, 28.19, 28.24, 30.59, 30.63, 30.72, 36.85, 37.08, 37.69, 45.53, 49.08, 49.08, 49.69, 54.47, 54.62, 80.17. 80.37, 155.46, 156.37, 174.68, 175.06. PAM resin from Bos-Ng-p-Tosyl-L-arginine (1.52 g, Bashem, 0.5 meq) was sabrered in a container developed for the manual synthesis of solid-phase peptides. The peptide was bent sesuensially and separated from the resin using the previously dessritos prosedimientos. Four equivalents of deactivated amino acids were used in the couplings. The deprotection are HF provided 480 mg of material srudo. Purification by HPLC (5-70% CH3CN, 0.1% TFA, gradient for 60 minutes, (20 mL / min) gave a total of 191 mg of the somatic compound 12 an insoluble lyophilate.

T.R. - 33.7 minutes (5-70% CH3CH, 0.1% TFA for 65 minutes, Cl? 5 ja, analytical solutum). LD-MS: salsulated 1307, ensonated 1308 (M + H). AAA: Arg 3.16 (3), Hyp 0.91 (1), Gly 1.00 (1), Thi *, Ser 0.99 (1), Tis *, NMsh *.

Example XIII Compound 13 -Gpa-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tis-NChg-Arg The Merrifield resin from Boc-Ng-p-Tosyl-L-arginine was hardened (4.20 g, Bachem RBos20, 0.48 meq / g), in a container designed for the manual synthesis of peptides, in solid phase. The peptide was screened to form a tetrapeptide (Aspulation Ser- (OBn), then the process was transferred to an automated peptide synthesizer CS-BIO for the adduction of Gly, Hyp, Pro, and Arg. A porsion of this peptidyl resin (0.53 gram) was removed from the reassuming filtrate.The resin sample was deprotected as TFA as it was previously dessribió and it was blown up with N- (Bos) -d-aminovalide using the prosedimiento dessrito previously for HOBT / diimida astivasión. Unprotected are trifluoroacetic acid, it was previously dessribió and neutralized washing sesuensially are dichloromethane, 10% diisopropylethylamine in dichloromethane, dichloromethane, and finally are DMF.The resin is heated a mixture of 0.566 g of lH-pyrazol-1-sarboxamidine (Bernatowisz , MS et al., J. Org. Chem. _57_ 2497 (1992)) and 0.76 mL of diisopropylethylamine in 20 mL of DMF at 47 ° C for 2.25 hours.The resin was washed is dichloromethane and dimethylformamide and the reassess are 1H-pyrazole-lsarboxamidine was repeated two additional times. The resin was washed sequentially with chlorodimethane, methanol, then it is dichloromethane and inessed in vacuo. The deprotession are HF provided 80 mg of the somatose 13 somo an insolid lyophilate. HPLC: T.R. - 22.6 minutes (5-55% CH3CH, 0.1% TFA for 50 minutes, C18 5 t analytical soluton). LD-MS: salted 1278 (M + H), embedded 1278.7 (M + H).

Example XIV Compound 14 &-Gpa-Pro-Hyp-Gly-Thi-Ser-D-Tis-NChg-Arg Merrifield resin from Boc-Ng-p-Tosyl-L-arginine (4.20 g, Bashem RBos20, 0.4 T mqq / g) was charged in a container designed for manual synthesis for solid-phase peptides. The peptide was bent sesuensially to form a tetrapeptide (As-binding Ser- (OBn)) then the process was transferred to an automated peptide synthesizer CS-BIO for the adduction of Gly, Hyp, and Pro. One portion of this peptidyl resin (0.260 gram) was removed from the reassuming filth. The resin was deprotected is TFA as previously disintegrated and an acid N- (Bos) -d-aminovalerose was blown off, using the above-discussed procedure for the astivation of HOBT / diimide. This residue was deprotected by acid, trifluoroacetic acid, previously disintegrated and neutralized by washing sesuensialemente are dichloromethane, 10% diisopropylethylamine in dichloromethane, disloroethane, and finally are DMF. The resin was heated to a mixture of 0.405 g of lH-pyrazole-1-carboxamidine (Bernatowicz, MS et al., J. Org.Chem 14 48-58 (1959)) and 0.545 mL of diisopropylethylamine in 14.5 mL of DMF a 47 ° C for 2.25 hours. The resin was washed are dichloromethane, and dimethylformamide and repeated reassessment are lH-pyrazole-1-sarboxamidine. The resin was washed sesuensially are dichloromethane, methanol, then dichloromethane and brazed in vasuo. Deprotession are HF provided 30 mg of compound 14 as an insoluble lyophilate. HPLC: T.R. = 22.3 minutes (5-55% C ^ CN, 0.1% FTA for 50 minutes, Cl? 5 m, analytical solution). LD-MS: salted 1123 (M + H), stipulated 1123 (M + H).

Example XV Compound 15 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tis-NPhg-Arg Fmoc-D-Tic Acid Chloride An equivalent of Fmos-D-Tis was dissolved in CH2CI2 (0.3M) and solosó in a fitted flask are a stir bar and reflux probe. Thionyl sluride (10 equivalents) is added, agitated and the mixture refluxed under nitrogen for two hours. The reassessed mixture was sonsentered by rotary evaporation and the residue was diluted with CH2Cl2 and concentrated again to remove or remove excess thionyl chloride. This was repeated twice and the resulting acid chloride was triturated with hexane (or alternatively the residue was recrystallized from CH2Cl2 / hexane) until a fine powder was obtained. This powder was used without additional purification. Fmos-D- Tis-N-enilglisine N-Phenylglycine (1.2 equivalents) was suspended in dry THF (0.5M) in a flask and three equivalents of diisopropylethylamine were added. The flask was solos in a water bath are ice and stirred for 15 minutes under nitrogen. An equivalent of slurry was dissolved from Fmos-D-Tisin THF seso (0.15M) and slowly added to the cooled flask. Immediately a presipitate was started and the reaction was allowed to warm to room temperature by stirring it for two hours. Once the reaction was completed, the solvent was removed by rotary evaporation and the residue was reslurried in ethyl acetate and washed with KHSO4., at 5%, and H2O, and brine. The sesado is Na2S04, rotating evaporation and the solosión under a high vasío produced a foam blansa. The dipeptide was analyzed by HPLC (Cl? RP solnum, 4.6 X 250mm, 1 mL / min of flow, 30 minutes of gradient 30-100% CH3CN / H20 are a 0.1% TFA, detession at 245nm) for purity It was used without additional cleaning. Bonding or Fixation of Fmos-D-Tis-NPhq-OH to Ars-OHMP resin The cleavage of the dipeptide Fmos-D-Tis-NPhg-OH (approximately 0.785 mmol) to the peptidyl resin (0.25 mmol) was carried out using Bop -Cl under previously dissonant sonsions for the asymmetries of protected aminoasides in the N-position, to the N-substituted aminoasides. Peptide Synthesis: Fmos-D-Tis-NPhg-Arg-OHMP resin was deprotected in N-position by reassessing it is 20% piperidine in DMF (2 x 30 minutes). Then the resin was washed sesuensially, three times are DMF two times are dichloromethane, two times with methanol, and two vesces are dichloromethane. The Fmos-Serine- (o-t-Bu) -OH was puffed using the Bop-Cl prosedimiento as previously dissed. The resin was then transferred to an automated ABI peptide synthesizer, model 431, the additional residues were ligated using standard FOS / HBTU priming procedures (ABI 431 Fmos procedure, Petrid Synthesizer Model 431 A user's manual from Applied Byosistems, version 2.0, January 1992). The resin was then washed several times with disulfomethane and dried under anhydrous nitrogen. The resin was then treated with 10 mL of trifluoroacetic acid, which contained 0.5 mL of thioanisole and 0.25 mL of hestanotithiol. The reassum was bubbled three hours at room temperature. The mixture was filtered and the resin washed is approximately one liter of the trifluoroacetic acid. The combined filtrates were concentrated in vacuo and the residue was treated with anhydrous diethyl ether and allowed to stand at the temperature of the ice bath for 15 minutes. Then the presipitate was collected by filtration and washed well under ether, cold anhydrous, and dried in vasuo resulting in 205 mg of insoluble powder. Purification by HPLC of a small portion of material (0-35% CH3CN, 0.1% TFA, gradient for 50 minutes, 10 mL / min) provided 10 mg of the 15-fold as a colorless lyophilate HPLC: R.t. - 20.9 minutes (5-55% CH3CN, 0.1% TFA for 50 minutes, Clß 5 m, analytical column). LD-MS: calcined 12T7.5 (M + H), embedded 12T7.5 (M + H). Correct data was obtained from the amino analysis.

Example XVI Compound 16 D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-NPhg-Arg The dipeptide Fmos-D-Phe-NPhg-Oh was prepared according to the method used to prepare the F oc-D-Tis-NPhg-OH in the somatic 15. The dipeptide Fmos-D-Tis-NPhg-OH (approximately 0.5 mmol) was swelled to the Arg-HMP resin (0.25 mmol) using the preparations for the 15th moiety. The peptide was synthesized, and separated from the resin as it was dessribe for the 15th moiety, to provide 260 mg of crude peptide. . Purification by HPLC of 75 mg of this material (5-50% CH3CN, 0.1% TFA, gradient for 60 minutes, 10 mL / min) gave 18.9 mg of the somatic 16 somo an insoluble lyophilate. HPLC: T.R. = 21.9 minutes (5-55% CH3CN, 0.1% TFA for 50 minutes, Cl? 5, analytical soluton). LD-MS: salted 1275 (M + H), 129T (M + Na); ensonated 1274 (M + H), 129T (M + Na).

Example XVII Compound 17 D-Arg-Arg-Hyp-Hyp-Gly-Thi-Ser-D-Tis-NChg-Arg The Merrifield resin of Boc-Ncr-p-Tosyl-L-arginine (4.2 g, Bashem, RBOC20, 0.4 T meq / g) was charged in a container designed for the manual synthesis of solid phase peptides. The peptide was pooled parsially and separated from the resin using the previously described procedures. Four equivalents of pre-added amino acids were used in the couplings. The deprotession are HF provided 1.05 g of raw material. Purification by HPLC of a small portion of this material (0-65% CH3CN, 0.1% TFA, gradient for 50 minutes, 10 mL / min) gave the somatic compound 17 an insoluble lyophilate. Sorrestos data of aminoásido and peptide sequence were obtained.

Example XVIII - Biological Data The most preferred compounds of the present invention are bradykinin antagonists and such are of wide utility for therapeutic intervention in disease state or in pathophysiological sondisiones, where the bradykinin sequestration is implied. The following protocols disclose assays that are used herein to determine the astivad antagonist to bradykinin, in vitro and in vivo, and assays to characterize the seledability and stability in vivo of various somatic depositions are the invention. Medisionßs of B2 antagonist asthma, in vitro The normal pA2 assay in rat uterus was tasted as follows: Sprague-Dawley rats, females (200-250 g) were pretreated with stilbesterol (100 Jfq / kq) and They were sacrificed 18 hours later by a blow on the saberza and they were bled. The uterine tubas were removed, they were solved under resting tension of 1 g in 4 ml tissue baths, which were dissolving from de Jalón at 31 ° C and were aerated. Surves of sonsentrasión-efesto for bradykinin were obstructed in the austerity and presensia of the antagonist (preinsubado during 15 minutes) the potency of the antagonist salsuló of sonformidad are the method of (Arunlakshana, 0. , Sshild, H.O., Br. J. Pharmasology 1_4_ 48-5T (1959)). Following the exposure to the highest concentration of antagonist (usually 10.5 molar), the tissue was washed at 10 minute intervals for 40 minutes, after which time a surva sonsension -effsto for bradykinin was built again. -log (molar sonsension that produced 50% of the original maximum response for bradykinin) for bradykinin at this time, was salsulated and somparaba are pD2 are the invisial surva of consensual-efesto control, for bradykinin. the values of pD2 somparada are sonogen, reflected the "percentage recovery" of the agonist response Medi cations of antagonist astivity to Bi in vitro New Zealand siblings, females, were sasrified by an overdose of pentobarbital (TO «iZg- iv) and the thoracic aorta was removed, spiral strips were mounted under a rest tension of 2 g, in tissue baths of 500 mL, which were in solution of Krebs (Na C] 108.3 mM, 4.7 mM KCl, 2.5 g CaCl2, 1.2 mM MgH04 KH2P0, 25 mM, 25 mM greasy, of indometasina 2.T mM) and aerated are a mixture of 95% 02/5% CO ?. Two surves of sonsentrasión-efesto for Arg'-bradikinina were manufactured at 1 and 3 hours. At 5 o'clock, des-Arg9-bradykinin was added to the bath, until a final 10"7 M. This produced stable, sustained and prolonged estrusions of up to 45 minutes.The IC50 or sonsension that produces 50% inversion of the contraction, it was then sampled from the resulting drawings or drawings.The results obtained are shown in Table 1.

Stability studies Plasma samples were prepared by the colessión or whole blood collection of healthy human volunteers, men and women or of sobayos. Samples 5 were collected in culture tubes that were heparin sodium, and then were centrifuged at 4 ° C at 2000 rpm for 10 minutes. The supernatant frassions were removed by aspiration and kneaded in vials or small bottles at -20 ° C. They prepared cortisal membranes of lung and kidney of rat or puersus, using differential rifugation as described by Skedgel (Boot, AG et al., Biochemisal Journal 142, 575-5T1 (1974)) for lung at Boot (Erdeos, EG et al. , Bioshemisal Pharmasology 1_3 3471-347T (1984)) for kidney. The membrane ester preparations were kneaded at -20 ° C. The bradykinin antagonists were diluted to a 1 mM sonion in PBS (0.0132 M phosphate, 0.1454 M NaCl, pH 7.2). 10 microliters of this working solution, in a series of Eppendorf tubes followed by human or guinea pig plasma (90 mL or PBS, as a sontrol test, and were incubated for several periods of time.) At any point of time, the reassessment suddenly cooled down. are the addition of 100 mL of IN HCl of either acetonitrile or ethanol.The samples were allowed to stand for approximately 15 minutes and were then rifuged at 14,000 rpm for 10 minutes.The supernatant frassions were removed, filtered through filters (Millipore). ) of 0.22 MM and analyzed by HPLC (Cl ?, asetronitrile in water 12-T0%, both containing 0.1% of trifluoroasetiso, inspecting at 214 nm.) Porcine kidney and lung preparations were diluted 1:10, with PBS the rat kidney preparations were diluted 1: 100 are PBS, the porsin lung preparations were diluted 1: 1 in PBS, the solutions of the bradykinin antagonist (10 mL were added to a series of Eppendorf tubes, followed by r membrane preparations, diluted, resistent 90 mL). At various time intervals, the reassumptions were suddenly quenched by the addition of 100 mL of ethanol, rifuged and analyzed by HPLC as previously dissorted. The half-life of the disappearance of the HPLC type was determined using a software program ENZFIT (Elsevier). The stability data are preed in Table 2.

Table 1: Antagonist astigmatism to Bradykinin, in vitro in tests, in funsional tissues.

B * Percent BA Compound for n Aorta (rat uterus) recoverConej o tion 1 5.67. ± 0.17 3 32 6.41 - 0. 25 3 2 6.76 ± 0.71 3 0 5.79 - 0. 065 3 6.41 ± 0.49 3 100 5 4 4 agonist < 5 4 9.5 i 0.05 10 71 < 5 3 6 7.3 ± 0.03 3 93 < 5 2 7 agonist 5 2 8 8.50 ± 0.09 3 56 45 4 9 7.73 ± 0.09 3 87 5.52 4 5.85 ± 0.09 3 75 5.34 4 11 agonist < 5 4 12 agonist 5 4 13 9.09 ± 0.25 10 66 14 7.65 ± 0.25 6 81 15 8.88 ± 0.12 6 54 16 7.68 ± 0.09 6 60 17 8.48 ± 038 5 60 CP-0589 * 6.9 ± 0.89 Not Analyzed Table 1 (sontinuasión) BÍ Percent Bi Compound pA2 n of Aorta of (rat uterus) recover- Rabbit _ ^ _____ tion CP-0661 * 7- ° ± 0.20 Not analyzed HOE-140? o.3 NOT analyzed analyzed Inactive + CP-05T9 D-Arg-Arg-Pro-Hyp-Tis-Gly-Ser-D-Tis-Ois-Arg * CP-0601 D-Arg-Arg-Pro-Hyp-Gly-Gly Ser-D-Tis- Oic-Arg Both compounds were synthesized through conventional methods of synthesis of peptides in solid phase, as dessribió for the positions from 1 to 12.

Antagonistic binding to the ileum of guinea pigs. Ileons of albino soba, male, of the Hartley strain, distalized servisalemte, were collected. The íleons were washed are cooled saline jet are ice, they were turned over, that is, they were inverted internal and external parts, and washed rubbing cotton gauze. The tissue was then thawed and kneaded at -70 ° C. When used, 35 g of ileons melted on ice were sorted or stepped finely are a tissue sorter and then were admission to 10 volumes (350 mL) of TES homogenization buffer (25 mm), pH 6.8) containing a protein inhibitor or cosset (1 M 1, 10-phenanthroline, 5 Mq / mL trypsin inhibitor, soybean inhibitor, 100 Mq / ta basitrazine, 1 mM benzamidine, and 100 mM fluoride phenylmethylsulfonyl). This mixture was homogenized in a PT-20 Brinkman polytron apparatus (adjusted at intervals of 7.4 x 20 seconds) and subjected to different stringency (1000 x g, 4 ° C, 10 minutes). The small pieces were discarded and the dissolution was again brought up to the volume using buffer for fresh homogenization and then sentrifuged for 15 minutes at 43,000 x g, 4 ° C). The trosites were suspended again in suficient form in buffer for homogenization, and were centrifuged as before. The supernatant was discarded again and the trosites were suspended in TES buffer (25 mm, pH 6.8) and sentrifuged 43,000 x g, 15 minutes). The final chips or pellets were resuspended in 5 volumes (165mL) of TES buffer producing approximately 2.0 mg of protein per mL and it was kneaded at -70 ° C until used. The insubasions were taken to taste from a total volume of 0.315 mL, which was 20 uL of solvated bradykinin marsada are titrio (0.3 nM) 20 uL of non-thickened sonol, drug or vehicle, 150 uL of test buffer ( 25 mM TES, pH 6.8 1 mM 1, 10 phenanthroline, 1 mM DTT, 2 mM saptopril, 140 mg / mL basitrasin, 100mM thiophane, and 0.1% bovine serum albumin, and 125 mL diluted membrane (diluted 1: 4 for a final 0.2 mg / mL end-of-the-end analysis to initial the binding.) The assay was conducted in polypropylene tube, and the samples were allowed to incubate at 24 ° C for 45 minutes.

The mixes were then quickly filtered through prefabricated GF / B Whatman glass fiber filters. (for more than 2 hours) are 0.1% polyethylenimine asuosa. The filters and tubes were subsequently washed, 8 porsiones of 1.0 mL of wash buffer, cooled in ice, which was 10 mM Tris (pH 7.5), 100 millimolar NaCl, and 0.02% bovine serum albumin. The radioassessment was determined by essintilasión sonate in liquids. Table 2 presents data for item 5, which is also designated as CP-0597, and for standards or standards.

Table 2. Summary of in vitro data HOE-140 CP-0597 CP127 Bradiqui nina B2 pA2 (rat uterus) 10.3 9.5 8.5 Binding B2 1.4 pM 1.3 pM 4.8nM (G.P.I) 30.1 pM Average life data > 6 h > 6 h human plasma N.D > 6 h 2.75 h rat kidney N.D. > 6 h 0.66 h 0.45 h porcine kidney * N.D. > 6 h > 6 h 0.13 h pig lung 0.15 h 0.05 h 0.05 h + NPC17761 1. 17 hours * NPC17731 4. 34 hours The CP-127 is a dimer dessrito in the Example 1 of the solisitud are No. of series 07 / ß59.5? 2, of the formula: CP-0127 The somatic is itself a highly asthmatic antagonist of bradykinin.

Biological data in vivo Blood pressure in sonejo Rabbits, masses, were anaesthetized from New Zealand, they are pentobarbital and cannulas were placed in the fermoral arteries for the record of blood pressure. The cannulae were colosated in the femoral veins for the injection of bolus or for the infusion of somatids. The fermentor artery satellites were conencted to a Gould pressure transducer and the blood pressure was recorded by presenting it in a multi-grap register, Grass. After a period of equilibrium, the specifie experimental development was initiated. BK2 ED50 - after stabilization of a stable baseline of blood pressure, the sonejos were administered bolus injections of bradykinin, the suals produced approximately a disminusion of 15 to 25% in blood pressure (0.2 and 0.4 nmol, iv) bradykinin was analyzed in the absence and then in the presensia of several doses of CP-597 (somatic) (0.01, 0.03, and 0.10 mg / Kg / min iv) for the determination of the ED50 (it is the dose of CP-0597 that reduse the maximum response to bradykinin by 50%). In this system it was determined that the ED50 was 0.051 ± 0.06 m / Kg / min 29.2 pmol / kg / min). Bk2ED5o - lymphoproliferase are lipopolysaccharide (LPS) of E. coli, (10 mg / aminal) intravenously from 11 to l? hours before the experiment. The preadistation of endotoxin resulted in the overregulation of BKi receptors in the tilting system, allowing the evaluation of BK2 antagonist astivity. The stimulation, both of the existing BK2 resepters, is that of the BKi inducers, produced hypotension. After equilibrating the blood pressure, the animals were administered bolus injections of bradykinin (0.2 and 0.4 nmol) and des-Arg9 bradykinin (4.0 and T.O nmol). Both agonists were analyzed in the absence and then in the presence of increasing doses of CP-5097 (1,3, Y 10 mG / kg / min). The ED50 for activity B i in this system was 2.9 ± 0.92 mg / kg / min (1.7 nmol / kg / min). HOE140 was inactive at doses up to 10 ug / kg / min. Selectivity of CP0597, intravenous After equilibrium in response to blood pressure, produced for asethylsoline (20 nmol), norepinephrine (20 nmol), substance p (20 pmol), angitensin (100 pmol), angiitisin II (2 pmol), bradykinin (200 pmol), each vasoactive agent was analyzed again after the administration of CP-0597 (0.1 mG / kg / min iv) and the preantagonist responses were somparo. In this study, the response to bradykinin was antagonized while that of the other vasoactive agents remained unaffected, compared to the controls.

Assay severity of CP-0597 infused intravenously CP-0597 (0.1 mg / kg / min) was infused intravenously for senescence experiments previously taught. After finishing the experiment of selestivity, the infusion of CP-0597 was stopped and the response to bradykinin (0.2 and 0.4 nmol) was analyzed at 5 min intervals, for the first 30 min, and at 15 min intervals until an hour was reached. At the time, after the infusion had been stopped, there was still 100% inhibition of the response to bradykinin. Rat blood pressure Spregue-Dawley rats, masho, were pentobarbital anaesthetized, and cannulae were solved between the fermoral arteries for recording the blood pressure. Selenulas were solved in both femoral veins for animal sada, for the administration of the test suites. The fermentor arteries were tested at a Gould pressure transducer and the blood pressure was recorded and presented on a Grass multigrade recorder. After a period of equilibrium, experimental prossification was initiated.

Seleptivity of subcutaneous CP-0597 After equilibrium of blood pressure, responses were produced to asetilsolin (20 nmol), norhepidrefina (1 nmol.} Sustansia p (2 pmol), angiotensin (20 pmol) angiotensin II (2 pmol) and bradykinin (20 pmol ai) The animals were then treated with CP-0597 (1.0 mg / kg sc) 30 minutes after the subcutaneous injection, the vasoactive agent was analyzed again and the responses of the preantagonists were analyzed. , the response to bradykinin was antagonized, while that of the other vasoactive agents remained untreated, with the sonotrophs in. Durasion of the assimilation of the bolus injections of CP-0597 intravenously After the equilibrium of blood pressure, responses were produced to bradykinin (10 and 20 pmol ai) somo sonol responses, then CP-0597 was administered as an intravenous bolus (either 3, 10 or 30 mg / kg) and the response was analyzed again. bradykinin at 5 minute intervals until the response returned to control levels. At 3 mg / kg the response was inhibited approximately 50% and had returned to the sontrol in 30 minutes. At 10 and 30 mg / kg, the response was inhibited. 100% is a return or return of 50% to the level of the sontrol, in 60 minutes, and to the total resuperasión of the response in 90 minutes.

Subsurface CP-0597 assession After equilibration of the blood pressure of the prinsipal artery, the animals challenged are bradykinin (10 and 20 pmol a.) To stabilize sontrol responses. The animals were then given subsumed injections of CP-0597 (1 AND 3 mg / kg s.s.). 30 minutes after the inception of CP-0597 and at intervals of 30 minutes, the animals were retested after bradykinin until the responses had returned to the sontrol levels. At doses of 1 mg / kg s.s.) the responses remained 100% inhibited three hours after the injection. At a dose of 3 mg / kg s. s., the responses were still inhibited 100%, 5 hours after the inception. Biological data in vivo are summarized in Table 3.

Table 3. Biological data in vivo for Example 5 (CP-0597) Example, Sections 5, 8, 13, 15, and 17 are highly potent antagonists are a potency that suggests a high propensity for efestos efisases as a pharmaceutic agent. It was found that compounds 4, 7, 11 and 12 are agonists, using rat uterus as a funtional tissue assay. Those experienced in tetanus will realize that agonists are also of potential value as cardioprotester agents. In addition, those experienced in the development of the bradykinin antagonist will understand that the compounds that are agonists in one type of tissue may be antagonists in another type of tissue. For example, Stewart described bradykinin antagonists containing D-PMhe at position 7 in the sequela of bradykinin. Stewart's antagonists based on data from the sobayo ileum which are D-Phe in position 6 and in position 7 such as NPC-360, turned out to be agonists in rat uterus (see U.S. Patent No. 4,693,993, and J). Stewart in bradykinin antagonists, Antagonist, Basis and Clinisal Researsh, p.60, 991). Effectorly, a similar phenomenon accompanies selesionate compounds in this dessripsión. For example, it was shown that compound 12 was an agonist in rat uterus tissue, but presented antagonist astivity in guinea pig ileum with an extremely stressful binding sperm (Ki-0.2 pisomolar and sobayo ileum). The compounds are a high degree of selestivity to the tissue, they can function as dual-agent pharmacological agents, where an antagonistic astivity may be desirable on a tissue but antagonistic astivity may be desirable on other tissues. These ideas add specifically to the development of cardioprotective agents. The most preferred embodiments of this invention are an aromatic D-amino acid in the 7-position and an N-substituted glycine., in the position?, wherein the substituent is cisloalkyl phenyl of moderate size. These analogs produce a DK2 antagonist astivity in certain types of tissues. The introduction of a methylene unit between the aromatic or sisalkyl ring inserves the propensity to agonist astivity in a number of tissue types. Similarly, N-bensilglisine or N-bensilglisine substituted in the ring in position 7 produced moderate potency antagonist, with the conditionality that in the position? a residue is present, which is formationally restricted, such as the Ois. If an addional methylene spacer or spacer is added to the N-substitution of the glisina, it is expected that the tension or elongation of the geometry produces agonists in similar tissues of similar interest, if the restricted residue, in the β-position is replaced by an unrestricted residue such as Leu 0 N-ChLg is expected to have a weak agonist astivity in tissue tissues of interest. The intrinsic value of selected replacements of N-substituted glycine residues, particularly those that are screened in the β-position, is that the judicious choice of the substituent has a tremendous effect on the binding of the sompt to the bradykinin receptor, where they are produced potent antagonists or binding agonists very stressed. The introduction of N-substituted glisina residues, allows the development of highly potent moléulas are very good properties for pharmaceutical agents. One of the important properties, given by the introduction of N-substituted glisins, is the stability to break or enzymatic cleavage. Table 2 illustrates the preferred stains are N-substituted glisina residues in the β-position, such as somatic 5, exhibit an extremely potent binding to the reseptor in selessioned tissues these analogues are more potent than bradykinin or that are such as antagonist CP-127 of bradykinin, dessrito in Example 1 of the solísitud of North American patent of property somún, are Serial No. 07 / ß59,5? 2. More importantly, table 2 illustrates the remarkable stability of the compound 5 to degradation, by means of important enzymatic systems. Peptide drugs are rapidly degraded by peptidases. In particular, the bradykinin-related molecules are rapidly degraded by aminopeptidases, carboxypeptidases (CP) and endopeptidases, such as neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The human plasma is riso in astividad of the peptidasa, the sual arises from the actions of the carbopeptidasa N, and of the aminopepetidasa M. The preparations dessritas in this dessripsión exhibit strong astividad of the protease enzyme, such somo dessribe later in the table .

Kidney of Kidney Lung of Puerso Puersus Rat Rat NEP ACE NEP ase ACE CP-M ACE nep Moprin sp-m Endopeptides a-24, 16 The stability tests summarized in table 2 represent in vitro analysis. The real stability of A single somatic set in kidney or lung tissue plasma, in a living animal, may vary. However, the in vitro test provides a reprodusible method for the sompasion of somatic tumors, without sasrifying large numbers of animals for experimentation in vivo. Thus, this battery of preparations of plasma and tissue, allows a broad analysis of the stability of the peptides, respecting the stability of the enzyme protease that can probably be found in a peptidic drug. He compound 5 is extremely potent, with a half-life greater than six hours, in all these analyzes. In comparison, bradykinin exhibits significantly lower stability. It also appears that the stannous 5 has greater stability than the CP-20 127. Other referensia scenarios such as NPC17761 and NPC17731, developed by Ssios-Nova, which have substituted proline residues in position 7 and Oic in position 8 , exhibited a lower stability, measurable, in crusial tests.

The data presented in Table 3 confirm the sorrelation between in vitro and in vivo analyzes. Enzyme 5 is exsepsionally potent in blocking the binding of bradykinin in BK2 resepters, in live sinejos (ED50 0.051 m / kg / min). In addition, the stacks 5 exhibit a substantial blockade astivity in BK1 blockade, in live sinejos (2.9 mg / kg / min). Both trials are extremely relevant to the hypotensive hypothesis of bradykinin in the toxic shock and are of interest for predesir efesto efisaz in the treatment of SIS / sepsis. Not only is the illustrated package potent, in live animals, the compound also exhibits long duration of assión (Rabbits 100% inhibited at 60 minutes, i.v.). In efesto, potencies were demonstrated that allow a somatic blockade of the efesto agonist until 5 hours after the subcutaneous dose (3 mg / kg, in rat). That stability of an agonist derived from a peptide is extremely unusual and demonstrates the propensity for good utility of agonists which are N 'substituted glycans, as pharmaceutic agents. Finally, studies were carried out using blood pressure models, both in sonejos and in rats, to demonstrate that the blockade of hypotensive efesto was re-stained are the blockade of the bradykinin receptors. The activity of other vasoactive agents, such as asethylsoline, norepinephrine, P substansia, angiotensin, and angiotensin II, were not afflicted by somatic 5.

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Sisuteri, F., Vasoneuroastive Substansias and their Implication in Pain Vassular, Res. Clin. Stud. Headache, 1: 6 (1967). 26. Cheronis, J.C., Whalley, E.T., Nguyen, K.T., Eubanks, S.R., Alien, L.G., Duggan, M.J., Loy, S.D., Bonham, K.A. and Blodgett, J.K., A new slase of Bradiquininba Antagonists: In Vitro synthesis and astivity in peptidic dimers of Bissussinimidoalsan, J. Med. Chem., 1563-1572 (1992). 27 Dray, A. and Bevan, S., TIPS, 14, 2T7 (1993). 2T. Stewart, J.M. and Young, J.D., Synthesis of Peptides in Solid Phase, (19T4). 29. Bodanszky, M. And Bodanszky, A., The Priestly Synthesis of Peptides, Springer Verlag, 19T4. Miklos Bodansky, Prinsipios of Synthesis of Peptides, Springer Verlag, (19T4).

. Barany, G. Et al, Synthesis of Peptides in Solid Phase, A Silver Anniversary Report, Int. J. Peptide Protein Res. 30: 705739 (19T7). 31. Tung, R.D., Rish, D.H., Dhaoan, M., J. Am. Chem. Soc. 107, 4342 (1985). 32. Cost, J., Peptides: events of the twenty-first European Symposium on Peptides (1990). 33. Beyermann, M. Bienert, M. Niedrish, H., Casrprino, L.A .; Sadat-Aalaee, D. Rapid synthesis, peptide synthase, via FMOC aminosetting and unblocking 4- (aminomethyl) piperidine, J. Org. Chem. 55, 721-728, (1990). 34. Carpino, L.A., Sadat-Aalaee, D., Chao, H.G., DeSelms, R.H., J. Am. Chem. Sos. 112, 9652 (1990).

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Bundgaard, H., Design of prodrugs, Elsevier (1985). 39. Porter, T.H. and Shive, W., J. Med. Chem. 11, 402 (1968). 40. Hill, J.T. and Dunn, F.W., J. Org. Chem. 30, 1321 (1965). 41. Proceedings ABI 431, Applied Biosystems Model, 431A Peptide Synthesizer User Manual, version 2.0, January 1992. 42. Bernatowisz, M.S., Matsueda, G. and Wu, Y., J. Org. Chem 57, 2497 (1992). 43. Arunlakshana, 0., Sshild, H.O., Br. J. Pharmasology, 14, 48-5T (1959). 44. Booth, A.G. and Kenny, A.J., Bioshemisal Journal 142, 575-5T1 (1974). 45. Erdos, E.G., Johnson, A.R., Skidgel, R.A., Bioshemisal Pharmasology 33, 3471-347T (19T4).

SEQUENCE LIST (1. GENERAL INFORMATION: (i) APPLICANT: GODDFELLOW, VAL S. MARATHE, MANOJ V. WHALLEY, ERIC T. FITZPATRICK, TNMOTHY D, KUHLMAN, KAREN G. (ii) TITLE OF THE INVENTION: PEPTIDES ANTAGONISTS OF BRADIQUININE THAT INCLUDE N-SUBSTITUTE GLYCINES (iii) SEQUENCE NUMBER: 8 (iv) SEQUENCE ADDRESS: (A) ADDRESS: CUSHMAN, DARBY 6 CUSHMAN (B) STREET: 1100 NEW YORK AVENUE, NW (C) CITY: WASHINGTON (D) STATE: DC (E) COUNTRY: U.S.A. (F) ZIP: 50005-3918 (v) READABLE FORM FOR THE COMPUTER: (A) TYPE OF MEDIA: FLEXIBLE DISK (B) COMPUTER: IBM COMPATIBLE PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) PROGRAMMING SYSTEM (SOFTWARE): PATENT IN RELAY NO. 1.0, VERSION NO. 1.25 (vi) CURRENT APPLICATION DATA: (A) NUMBER OF APPLICATION: US 08 / 208,115 (B) DATE OF SUBMISSION: 09-MARZ -1994 (C) CLASSIFICATION: (viii) ATTORNEY / AGENT INFORMATION: (A) NAME: KOKULIS, PAUL N. (B) REGISTRATION NUMBER: 16,773 (C) REFERENCE NUMBER / DOCUMENT: 203567 / DKT. 14 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (202) 861-300 (B) TELEFAX: (202) 822-0944 (C > TELEX: 6714627 CUSH (2) INFORMATION FOR SEQ ID NO: l (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 AMINO ACIDS (B) TYPE: AMINOACIDO + (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (ii) TYPE OF MOLECULE: PEPTIDE (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: l Arg Pro Pro Gly Phe Ser Pro Phe Arg 1 5 (2) INFORMATION FOR SEQ ID NO: 2: (1) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 AMINO ACIDS (B) TYPE: AMINO ACID (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (ii) TYPE OF MOLECULE: PEPTIDE (xi) DESCRIPTION PE THE SEQUENCE: SEQ ID NO: 2 Xaa Arg Pro Xaa Gly Xaa Ser Xaa Xaa Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO: 3 (I) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 AMINO ACIDS (B) TYPE: AMINO ACID (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (II) TYPE OF MOLECULE: PEPTIDE (XI) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3: Xaa Arg Pro Xaa Gly Xaa Ser Xaa Xaa 1 5 (2) INFORMATION FOR SEQ ID NO:: (I) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 AMINO ACIDS (B) TYPE: AMINO ACID (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (II) TYPE OF MOLECULE: PEPTIDE (XI) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4: Xaa Pro Xaa Gly Xaa Ser Xaa Xaa Arg 1 5 (2) INFORMATION FOR SEQ ID NO: 5: (I) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 AMINO ACIDS (B) TYPE: AMINO ACID (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (II) TYPE OF MOLECULE: PEPTIDE (XI) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5: Xaa Arg Xaa Xaa Gly Xaa Ser Xaa Xaa Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO: 6: (I) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 AMINO ACIDS (B) TYPE: AMINO ACID * (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (II) TYPE OF MOLECULE: PEPTIDE (XI) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6: Xaa Ag Pro Xaa Xaa Gly Ser Xaa Xaa Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO: 7: (I) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 AMINO ACIDS (B) TYPE: AMINO ACID (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (II) TYPE OF MOLECULE: PEPTIDE (XI) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 7: Xaa Arg Pro Xaa Gly Gly Ser Xaa Xaa Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO: 8: (I) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 AMINO ACIDS (B) TYPE: AMINO ACID (C) TYPE OF HEBRA: INDIVIDUAL (D) TOPOLOGY: LINEAR (II) TYPE OF MOLECULE: PEPTIDE (XI) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 8 Xaa Arg Pro Xaa Gly Phe Cys Xaa Leu Arg 1 5 10 It is noted that in relation to this date, the best method known to the applicant to implement the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims (27)

1. A peptide that is a bradykinin antagonist, characterized in that it contains one or more N-substituted glycine residues in the peptide chain.

2. A peptide that is a bradykinin antagonist, according to claim 1, characterized in that the antagonist is defined according to the following formula: Z'-Z ° -Aa-B2-C3-D4-E5-F6-G7- Hß-I9-J10 wherein: Z 'is optionally absent, but if present, is a hydrogen, acetyl, adaiuantylcarboxyl, ada antilacetyl, (Cl to C8) -alkyl, -alkanoyl, arylsulfonyl or alkoxycarbonyl group, or a derivative of a dihydroquinuclidini-1-carboxylic acid; Z ° and A1, which may be the same or different, are selected from the group consisting of a direct bond, hydrogen, an amino acid residue derivative comprising D or L of arguimin, D or L licina, D or L ornithine, H2H (NH «C) NHCH2CH2CH? (CH2) nC0- where n = »0 to 3, or substitutes for arguinin with the proviso that Z ° is different from a direct link when Z 'is absent; Bz and Cs, they can be the same or different, they are proline, hydroxyproline, sacosine, serine, threonine, N-methyl-serine, N-methyl-threonine, N-methylphenylalanine, glycine, and NR'CHR''C0, where R 'and R "is selected from hydrogen, straight or branched chain alkyl groups, from 1 to 8 carbon atoms, cycloalkyl from 3 to 8 carbon atoms, aryl, heteroalyl, and alkylamino groups; D * is glycine, alanine, or trienylalanine; B2 C3 D4 E5 can be replaced by -NH (CH2) nCO- where n is an integer from 4 to 14, E5 is phenylalanine, phenylalanine substituted with methyl, glycine, cyclopentylglycine, cyclohexylglycine, cyclohexylalanine, 2- indanglicine, thienylalanine, N- (2-indan) licina or N-substituted glycine wherein the substituent is alkyl of 1 to 4 carbon atoms, cycloalkyl, CH * Ar or CHaCHßAr where Ar is aryl, alkylthienyl, or an aromatic amino acid or an aromatic amino acid substituted on the a-nitrogen or a-carbon with methyl or ethyl; Fß is an amino acid aromatic spherical; G7 is an aromatic amino acid selected from the group consisting of D-Tic, D-Dic, D-phenylalanine, 2-indanglicin, D-cyclopentylglycine, D-cyclohexylglycine, D-proin and proline substituted at position 3 6 4 with alkyl, aryl, thioalkyl, thioaryl, oxyalkyl or oxyaryl substituents, and a N-substituted glycine residue wherein substituted groups is aryl, alkylaryl group, -CH2R, or -CH2CH2R wherein R is indane, indole, naphthyl or phenyl; Hß is an amino acid residue of the following structure: CHRiCO- wherein - 1 to 6, and R_ is alkyl of 1 to 12 carbon atoms substituted or unsubstituted, cycloalkyl of 3 to 8 carbon atoms, substituted or unsubstituted, unsubstituted or substituted monocyclic aryl or polycyclic aryl, heteroaryl, or heterocyclic, which contains one or more ring of three to eight atoms, selected from carbon, nitrogen, oxo or sulfur; R t is H, methyl or higher alkyl, or a neutral, acid, or basic alkyl, or an aromatic amino acid side chain; I9 is absent or a direct bond, OH, an amino acid, or H2N (NH = C) NHCH2CH2CH2 (CH2) "-NH-, where n = oa 3, or a substitute for arguinin with the proviso that I3 is different from OH when J10 is present and absent or different from a direct link when J10 is absent; and J10 is absent or, if present, is OH or an amino acid -OR or -NHR where R is alkyl.

3. The bradykinin antagonist according to claim 2, characterized in that Z 'is hydrogen

4. The bradykinin antagonist according to claim 2, characterized in that Z ° and A2 are the same or different and are selected from the group consisting of L-argininin, D-argininin, in H2N (NH-C) NHCH, CH * CH2 (CHa) "-C0-, wherein n - 0 to 3, and a substitute for arguinin consisting of analogues or homologs of arguinin, ornithine or lysine containing alkylamines, benzamidine, piperidine, alkylguanidine or alucylphosphonium moieties.

5. The bradykinin antagonist according to claim 2, characterized in that B2 and C3 are the same or different and are selected from the group consisting of proline and hydroxyproline.

6. The bradykinin antagonist according to claim 2, characterized in that D * is glycine.

7. The bradykinin antagonist according to claim 2 characterized in that E5 is phenylalanine, cyclopentylglycine, cyclohexylglycine or thienylalanine.

8. The bradykinin antagonist according to claim 2, characterized in that F6 is serine, cysteine, substituted serine or cysteine, wherein the substituted side chains are selected from the group consisting of N- (alkyl) -succinimidyl, N- ( alkyl) pyrrolidone, alkyl of 1 to 20 carbon atoms, alkenylalkyl of 2 to 20 carbon atoms, aryl, and alkylaryl.

9. The bradykinin antagonist according to claim 2, characterized in that G1 is D-Tic, D-phenylalanine, D-cyclopentylglycine, or D-proline substituted at the 4-position with alkyl, aryl, oxyalkyl substituents, or a glycine N residue. -substituted, wherein the substituted group is aryl, alkylaryl or -CH2R, wherein R is indane, indole, naphthyl or phenyl.

10. The bradykinin antagonist according to claim 2, characterized in that B2 C3 D * E5 is NH (CH2) nC0 where n "= 4 to 14. eleven - .

11 - The bradykinin antagonist according to claim 2, characterized in that Ri is an aryl, heteroaryl or substituted cycloalkyl group containing one to four substituents selected from the group consisting of amino, hydroxy, mercapto, inercaptoalkyl, alkyl groups , oxyalkyl, alkyloxy, carboxyloxy, halkogen, trifluoromethyl, trifluoromethoxy, aminoalkyl, alkylamino, or carboxamide groups.

12. The bradykinin antagonist according to claim 2, characterized in that I9 is arguinin or licina, or a substitute of arguinin consisting of analogs or homologs of arguinin, ornithine, or lysine containing alkylamines, benzamidine, piperidines, alkylguanidines or alkylphosphonium moieties.

13. A bradykinin-like peptide characterized in that it contains an N-substituted amino acid selected from the group consisting of N-cyclopentylglycine, N-cyclohexylglycine, N-phenylglycine, N-phenethylglycine, or N-methylcyclohexylglycine.

14. A bradykinin-like peptide, characterized in that it contains an N-substituted amino acid at position 8, wherein the substituent does not form a ring containing the N-substituted amino acid a-carbon.

15. A brachydinin antagonist according to claim 2, characterized in that: R 1 is cyclopentyl or cyclohexyl, phenyl or an alkyl-indane derivative.

16. The compound according to claim 2, characterized in that it is defined as or follows: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic- (NR) Gly-Arg or D-Arg-Arg- Pro Hyp-Gly-Thi-Ser-D-Tic- (NR) Gly wherein R, is substituent of the glycine residue, is cyclohexyl, substituted with methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, normal or isopropyloxy , CH2OCH2CH3, CH2CH20-CH (CH3) 2, CHaCH30CHa, CH2CH2OCF3, thiomethyl, thioethyl, thiopropyl (normal or isopropyl).

17. The compound according to claim 2, characterized in that sß is defined as follows: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NChg; D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-Igl-NChg-Arg / D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-NChg-Arg; or D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-Cpg-NChg-Arg.

18. The compound according to claim 2, characterized in that it is defined as follows: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NChfg-Arg; or D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NCpg-Arg.

19. The compound according to claim 1, selected from the following: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-NBng-Oic; D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-NBntg-Oic-Arg; or D-Arg-Arg-Pro-Hyp-Gl and-Thi-Ser-D-NBng-NChg-Arg.

20. The compound according to claim 1, characterized in that it is selected from the following: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-NPeg-Oic-Arg; or D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NMch-Arg.

21. The compound according to claim 2, characterized in that it is selected from the following: # -Op »-Ar« -Prß-Hyp-aly-thi- * ««, 0-Tiß -? - Wg-? Rflí * -? Pa * Prc »* - Hy? -? Ly-Thi-ß« rD-tio »l? cg-Ar9; IHl | M - A-r «-Frß-Hyp-ßly-1? I-f» r-D-Ti? »| IClμij ß # -oé-pro-Hyp-eiy-? I -?« R * o ^ Plg-Hch9.

22 The compound according to claim 2, characterized in that it is selected from the following: D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-NPhg-Arg; or D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-NPhg-Arg.

23. A method for treating pathological conditions, wherein the bradykinin or a closely selected metabolite is a known pathogen, mediator or hormonal signal, characterized in that it comprises administering a therapeutically effective amount of the compound according to claim 1.

24. The method according to claim 23, characterized in that the pathological condition is pain or inflammation.

25. A method for treating a cardiovascular dysfunction, characterized in that it comprises administering a therapeutically effective amount of the compound according to claim 1.

26. The method according to claim 25, characterized in that the cardiovascular dysfunction consists of istemia, vessel damage or cardiovascular tissue damage.

27. A peptide according to claim 1, characterized in that from 8 to 10 amino acid residues, wherein the amino acid residues at position 8 and / or 9 is a residue of N-substituted glycine, wherein the positicioneß are numbered sequentially to from the N-terminal end.