MXPA96005870A - Endothelin antagonists ii - Google Patents

Abstract

Novel antagonists of endothelin containing an N-terminal fragment (I) are described, as well as methods for the preparation and pharmaceutical compositions of the same, which are useful in treating elevated levels of endothelin, acute and chronic renal failure, hypertension, myocardial infarction, metabolic, endocrinological, neurological disorders especially cerebral vasospasm, stroke, and head injury, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease, restenosis, angina, cancer, pulmonary hypertension, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes.

Description

ENDOTHELIN ANTAGONISTS II BACKGROUND OF THE INVENTION The present invention relates to novel endothelin antagonists useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions including these compounds and a pharmaceutically acceptable carrier and to pharmaceutical treatment methods. in particular, the novel compounds of the present invention are endothelin antagonists useful in the treatment of high levels of endothelin, chronic and acute renal failure, hypertension, myocardial infarction, metabolic, endocrinological and neurological disorders, especially cerebral vasospasms. jpttaques and head injuries, congestive heart failures, endotoxic attacks. subarachnoid hemorrhages. arrhythmias, asthma, preclaimsia, arteriosclerosis disorders including Raynaud's disease, restenosis, angina, cancer, pulmonary hypertension, ischemic disease, damage to the gastric mucosa, hemorrhagic attack, ischemic bowel disease and diabetes.

Endotilene-1 (ET-i). A potent vasoconstrictor, is 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1 is one of a family of structurally similar bicyclic peptides that includes; ET-2, ET-3, vasoactive intestinal contractor (YIC) and sarafotoxins (SRTXs). The only bicyclic structure and corresponding arrangement of the disulfide bonds of ET-1, which are the same for endothelin, V1C and sarafotoxins. has led to significant speculation as to the importance of the resulting induced secondary structure for receptor, binding and functional activity. The ET-1 analogs with incorrect disulfide pairs exhibit enú-, 100-fold less vasoconstrictor activity. The flexible C-terminal hexapeptide of ET-1 has been shown to be important for binding to ET receptor and functional activity in chosen tissues. In addition, the terminal amino acid R (Trp-21) has a critical role in the binding and vasoconstrictor activity, since ET (1-20) exhibits approximately 1000-fold functional capacity Endothelin is involved in many human diseases.

Several studies in vi \ o with ET antibodies have been reported in disease models The left coronary artery ligand and reperfusion to induce myocardial infarcts in the heart of rats, caused an increase of four to seven fold in endothelin levels endogenous It was reported that administration of ET antibodies reduces infarct size in a dose-dependent manner (Watanabe T., et al., "Endothelin in Myocardial Infarcts." Nature (London), 344.14 (1990)). Thus, ET may be involved in the pathogenesis of congestive heart failures and myocardial ischemia (Margulies K B, et al, Increased Endothelin in Experimental Heart Failures, Circulation, 82 2226 (1990)) Studies by Kon and colleagues using anti-ET antibody in an ischemic kidney model, to deactivate endogenous ET, indicated the intervention of ET in acute renal ischemic lesions (Kon V, et al. "Endomerin Glomerular Actions in vivo" J Clin. ., 83 1762 (198M)) In isolated kidneys, preexposed to specific anti-endothelin antibodies and then challenged with cyclosporine. renal perfusate flow and glomerular filtration rate increased, while renal resistance decreased compared to kidneys pre-exposed to unimmunised rabbit serum. The effectiveness and specificity of the EF anu antibody were confirmed by their ability to prevent renal deterioration. by a single dose of a single bolus (150 pmol) of synthetic ET, ptero not by infusion of angiotensin II. norepinephrine or thromboxane A2 mimetic U-46619 in isolated kidneys (Peyico et al., "Endothelin mediates Renal Vasoconstriction Induced by Cyclosporin in the Rat 'J. Am. Soc. Nephrol., 1:76 (1990)).

Others have reported the inhibition of vasoconstriction induced by ET-1 or ET-2 in thoracic aortas of isolated rats using a monoclonal antibody to ET-1 (Koshi T., et al., "Inhibition of Vasoteconstriction induced by Endothelin (ET-). 1) and ET-2 by I JÉ Anti-ET-1 Monoclonal Antibodies "Chem Pharm. Bull., 39: 1295 (1991)).

The combined administration of ET-1 and ET-2 antibodies in rabbits showed significant inhibition of responses in blood pressure (BP) and renal blood flow (Miyamori I., et al .. Systematic and Regional Effects of Endothelin in Rabbits: 15 Effects of Endothelin Antibody "Clin. Exp. Pharmacol. Physiol., 17: 691 (1990)).

• Other researchers have reported that the infusion of specific ET antibodies into hypertensive rats simultaneously (SEIR) decreased the main blood pressure (MAP) and increased the rate of glomerular filtration and renal blood flow. In the control study with normal-tension Wistar-Kyoto rats (WKY) there were no significant changes in these parameters (Phno A. Endothelin and Endothelin Specific Antibody Effects in Hypertensive Rats Spontaneously. "1 Tokyo Women's Med. Coll., 61: 951 (1991)).

In addition, the endothelin levels have been reported in several disease states (See Table I below).

Burnet and colleagues recently demonstrated that the exogenous infusion of ET 5 (2.5 ng / kg / ml) to anesthetized dogs, which produce double the circulating concentration, had biological actions (Lerman A., et al. "Endothelin has Biological Actions in Pathophysiological Concentrations Circulation 83. ISS (1991)) Thus, cardiac output and cardiac output decreased in association with increased renal and systemic resistances and antinatriuresis These studies support a role for endothelin in the regulation of cardiac regulation. cardiocular, renal and endocrine fixation.

In the anesthetized dog with congestive heart failure, a significant elevation of two to three doubles of circulating ET levels has been reported (Cavero P.G., et al., "La Endothelin in Cardiac Failures. Experimental Congestives in the Anesthetized Dog, "1 Am. J.

Physiol., 259 F312 (1990)) and human studies have shown similar increases (Rodeheffer RJ, et al., "Endothelin in Circulating Plasma Correlates with ß áf Severity of Congestive Heart Failure in Humans Am. J. Hypertension- 4: 9A (1991).) When Chronic ET Infusions were Made In male rats, to determine whether a long-term increase in circulating ET levels would cause a sustained elevation or rise in the arterial blood pressure, significant, sustained, and dose-dependent increases in the arterial BP were observed. similar with ET-3 despite the fact that larger doses were required (Mortenson LH et al., "Chronic Hypertension Produced by Infusion of Endothelin in Rats'" Hypertension, 15: 729 (1990)).

The distribution of the J subtypes of doped leceptoi, named ET ?. and ETB, it Sp studied extensively (Aiai H. et al \ atuialeza 348739 (1990), Sakurai T, et al, Nature, 348732 (199oi The ET \ or vascular soft muscular leceptoi is distributed widely in tissues ca? Ascers v in six regions of the brain (Lin HY, et al, Proc Nati Acad Sci, 88> 1S (1991)) The ETBI lectern, originally cloenened from rat lung, has been praised in rat cecelia. in endothelial cells, although it is not known whether the ETB icepitters are equal to these sources. The subtypes of human ET receptors have been expressed (Sakamoto A, et al, Biochem lOβBiophys Res Com) 78-6> (1991), Hosoda k et al FEBS Lett 178656 (1991)) The ET-receptor clearly mediates vasoconstriction and there have been some reports that imply that the ET receptor "in the answer \ asod" the initial step to the ET ( Takayanagi R, et al, FEBS Lett, 282103 (1 1)) However, recent data show that the ETB receptor can also mediate \ soconstpccion in some tissue beds (Panel RL, et al, Biochem Biophys Res Co mun 183 (2) 60 (! E > °)) Comparison of receptor affinities of ETs and SRTXs in rats and atria (ETA) or cerebellum and sea horse (ETB) indicate that SRTX-c is a selective ETB ligand (Williams DL, et al Biochem Bioplns Res Commun , 175556 (1991)) A recent study showed that selective ETB antagonists only caused vasodilation in the aoitic ring of iatas, possibly through the release of EDRT from the endothelium (ibid). Thus the selective ETH antagonists reported, for example, the linear analogue TE [1, 3, 11 I-Ala] and thi uncos analogs ET [6-21, 1 3, 11, 15-Ala], ET [8-21, 11, 15-Ala] and N-AcetiI-EI [10-21, 11 l ^ -Ala] caused vasorelaxation in intact and isolated endothelium porcine pulmonary arteries (Saeki T et al .. Biochem. Biophys. Res. Commun .. 179 286?! L) U l)) However, some ET analogues are potent in the pulmonary artery of the rabbit, a tissue that appears to possess a type of ETB receptor and non-selective (ibid). 5 Levels of endothelin-1 in plasma increased dramatically in a patient with malignant hemangioendotelione (Nakagawa K .. et al .. Nippon Hifuka Gakki Zasshi, 100: 1453-1456 (199U)) lujfl The ET BO-123 receptor antagonist has been shown to block bronchoconstriction and contraction of the soft tracheal muscle induced by ET-1 in allergic sheep providing evi- dence of the expected efficacy in bronchopulmonary diseases such as asthma (Noguchi, et al. Rev. Respir Dis., 145 (4 Part 2): A858 (1992)). fifteen Circulating endothelin levels are elevated in women with preclampsia and serum and measures of renal dysfunction. These observations indicate a role for ET in renal constriction in preclaimsia (Clark B.A., et al., Am. J. Obstet Gynecol .. 166: 962-968 (1992)). 0 The immunoreactive endothelin-1 concentrations of asthma are elevated in patients with sepsis and correlate with the degree of disease and depression of cardiac output (Pittett J, et al .. Ann Surg. 213: (3V262 (1991)).

In addition, the antagonist of ET-1 BQ-12 > has been evaluated in a mouse model of endotoxic attack This ET antagonist significantly increases the rhythm of 9-t Psurvival in this model i I oshiaki M et al 20 1 90 EP 0 436 189 Al) Endothelin is a poiuite antagonist in the liver causing at the same time Sustained vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output (Gandhi C B, et al Diano of Biological Chemistry, 265 (29) 17432 (1990)) In diabetic rats sii eptozoticins there is an increased sensitivity to endothelin-1 (Tammesild P et al, Clin Exp Phai macol Physiol 19 (4) 261 (1992)) In addition, increased levels of ET-1 in plasma have been observed in patients with Mellitus. insulin-dependent diabetes icroalbuminunca indicating a role for ET in endocrine disorders such as diabetes (Colliei A, et al, Diabetes Care, (8) 1038 (1992)) It has been found that blockade of the ET- antagonist receptor. produces a antihypertensive effect in models of reniña normal a b < i |? of hypertension with a course of * C time similar to the inhibition of the responses induced by ET-1 (Basil M K, et al, J Hypertension, 10 (suppl 4) S49 (1 92)) Endotheliums have been shown to be arrhythmogenic and have positive chronotropic and inotropic effects, it would be expected that the blockade of the 0 ET receptor was useful in the analysis of cardiovascular diseases (Han S -P- et al, Life Sci, 46 767 (1990)) The broad localization of the endothelium and its lecei.toies in the central nervous system and cerebrovascular circulation has been deduced from RK, et al, Drugs Today, 28 (5): 303-3 10 (1992)) The immunity of the ET-1 enteral ebrov in rats has been shown to produce v anos effects of Behavior These factors strongly suggest a role for neurons in the neurological The powerful vasoconstrictive action of ETs and bi cepal artepolas suggests the importance of these 5 peptides in the regulation of cerebrovascular tone The increased levels of ET they have been reported in some CNS disorders. In the CSF of patients with subarachnoid hemorrhages and in the plasma of women with pi eclamsia, stimulation with ET-3 under conditions of hypoglycemia has been shown to accelerate the development of striatal damage as a result of an influx of extracellular calcium. has suggested that circulating ET or LdjíÉß produced locally with buve to the regulation of brain fluid balance through effects on the colloidal plexus and the pi oduction of CSF The development of ET-1 induced lesions in a new model of Local ischemia in the brain has been described.

The endothelial immunoreactivity of tissue and circulating tissue increases more than double in patients with arthroplastyJei osis aanzada (Lerman A. Et al, New England J Med., 325: 997-1001 (1991)) Endothelin immunoreactivity has also been associated -Bfincremented with the illness of Buergei Kanno K. et al, J. A er. Med Assoc, 264: 2868 (1990)) and the Raynaud phenomenon (Zamora M R et al, Lancet, 336: 1 144-1147 (1990)). Similarly, increased concentrations of endothelin were observed in 0 hyperchlorosterolidemic rats (Horio T. et al Arteriosclerosis 89 239-245 (1991)).

An increase in circulating enciotelin levels was observed in patients who underwent angioplasty crowns.] Ansiummal pei cutaneous (PCTA) (Tahara A et al., Metab Clin. Exp., 40 1235- 1237 (I 9 ^ ¡) Sanjay K, et al Circulation 84 (Supple 4) 726 (1991)) Inciterated plasma levels of endothelin in rats have been measured (Stelzner TJ,. {Hit al, Am J Phvsiol 262 I Mii f- »20 (1991)) and individuals (Mivauchi T. et al, Jpn J Pharmacol, 58279P (1992) v Si ait DI et al Ann Internal Medicine 114464-469 5 (1991)) with pulmonary hypertension High levels of endothelin have also been measured in patients suffering from ischemic diseases of the coiazon (Yasuda M et al, Amer Heart J, 119801-806 (1990), Ray SG, et al, Bi Hea.t I 673S 386 (1992). )) and whether it is stable or unstable angina (ijftstewart JT, et al., Br Heai t I 667-9 (1991)) Infusion of an anti-endothelin agent 1 hour before v 1 hour after a period of 60 minutes of isacaema resulted in changes in renal functions against the control In addition a? Nc? Emu? S > -n the tactility of activation of glomerular plaques was attributed to endothelin (Lopez-fane A, et al, J Physiology, 444513-522 (1991)) In patients with renal failure as well as in patients undergoing ßwiemodialisis treatment On a regular basis, endothelin levels of main plasma were significantly incised (Stockenhuber F et al Clin Sci (Londies) X2255-258 (1992)) Furthermore, it has been suggested that the master piolite effect of the endothelium on the masangial cells may be a contributing factor in the ciomcas là ± ana failures (Scuitz P J. J Lab Clin Med, 119448-449 (1992)) It has been shown that the local arterial administration of endothelin induces slight damage to the intestinal mucosa in patients on a dose-dependent manet (Mirua S, et al, Digestion 481"! - 172 (! &";, , The endothelialization of endothelium-1 in the range of 50-500 pmol / kg within the left gastuca anuia mci emento the release of activator tissue-type laminogen and the formation of activation of platelets and induced haemorrhagic change of the mucosa gastp? a in a dose-dependent manet (Kurose I, et al, Gut, 33868-871 (1992)) It has also been shown that an anti-ET-1 antibody reduced the vasoconstriction induced by ethanol in a concentration dependent (Masuda E, et al. Am J Ph Si 262 G78-G790 (1"92)) Elevated endothelin levels have been observed in patients suffering from Crohn's disease and ulcerative colitis (Murch SH et. to the Lancet ^. -, if-3S4 t 1 ^)) The role of endoelmas (ET-1 -2 -3) in vain physiological and pathophysiological conditions has been extensively studied (Doheitv AD Endothelin A New Challenge, J Med Chem 351493 (1992) Simonson MS Endothelins Multifunctional Renal Peptides Journals Physiologies ~ 3 J (1991)) These peptides act through their viz ET and ETB receptors, which have been cloned and expressed ETA-specific antagonists have been identified viz BQ? 2 (Ishikaua K Ti kami T, et al.) Endothelin cyclic pentapeptide antagonists , High selectivity The modifications that increase potency and solubility, J Med Chem s 2139 (1992) Kivoftimi I, et al, Endothelial antagonist cyclic pentapeptides EPA 0436189 To published on July 10, 1991), BMS182874 (Ste ? n PD et al of the endothelin of Sulfanamide EP 0558258 Al, published on lc de Sepiiembie de lc >; 'í) v FR 13 «> 17 (Keiμ H, et al.) Peptides having antagonist activity of the uidotelma a piocesi for the preparation of same and pharmaceutical compositions comprising them EP 04 ^ 7195 A2, published on November 21, 1991) ETi antagonists? v IT nonselective have also been identified even PD I 2X ° - if 'ody W L. et al .. Design of a hexapeptide antagonist of endothelin. J. Med. Chem. ^? | (1992). Dohertv A M. et al .. Structure-βPactivity Relationships of the Heptapeptide Antagonists of Terminal Endothelin C, J. Med. Chem., 36: 2585 (1993)). PD I 45 ('(.s) The rational design of a highly potent antagonist of the combined ET? And ETH receptor (PD 145065) and related analogs, Med. Chem Res. 1 4 (1993) Dohert AM, et al .. In vitro and In vivo Studies with a series of endothelin hexapeptide antagonists, J. Cardiovasc Pharmacol, 1993, in press), Ro 46-2002 (Burri K .. et al .. Application of sulfonamides as therapeutics and new sulfonamides EP 05 10526 A l, published October 28, 1992; M., et al., The discovery of Ro 46-2005, a non-peptide antagonist available orally from ET • recipients, and ETB, 3rd International Symposium of Endothelin, Houston, Texas, February 1993: Clozel \ l et al .. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. , 365: 759 (1993)) and Ro 47-02u3, a new endothelin receptor antagonist reverses the chronic vasospasm in experimental subarachnoid hemorrhages. Circulation, 4 (part 2, Supplement): 1- 170 (1992)) These antagonists have blocked vasoconstrictor effects For example. BO 123 has been effective in antagonizing the response driven by ET-1 0 in conscious rats (Ihara? L et al. Biological profile in vitro of the new and highly potent selective BQ 123 endothelin (ET) antagonist, J. Cardiovasc Pharmacol .. 20 (S 12): S 1 1 (1992); Ihara M., et al .. PerliK biol gics of new and highly potent endothelin antagonists selective for ET receptor? Life Sci .. 50 : 247 (1992)). The intravenous infusion of BQ 123 decreased blood pressure significantly in hypertensive rats with spontaneous psionic attacks and was effective in the prevention of pulmonary hypertension? Nd? U, or acute hypoxia (McMahon EG, et al.) Effect of ßrasforamidon (inhibitor) of the enzyme that converts endothelin) and BQ123 (antagonist subtype A of the receptor of the otelotelma) in blood pressure in hypertensive rats, Am. J 5 Hypertension, 6667 (1 9311 La. Constriction induced by ET-1 in rabbit retinal arteries and the rat vasculai resistance in rats was blocked by iv BQ123 (Takei K, et al., Analysis of the asocmtiactil response of endothelium-l in rabbit retinal vessels using an ET-1 receptor antagonist and a receptor antagonist. ETB, Life Sci., 53: PL111 (1 93)) Cycles) rina A (CsA) induced the release of ET-1 in vivo (Fogo iß A., et al. kidney transplant receiving ciclosporin a, Transplantation. 49 M 0 (1 90), Watchinger B. et al. The toxicity of Cyclosporin A is associated with reduced endothelin immunoreactivity in the renal endothelium, Transplant Pi oc 242618 (1992). Avvazu M. et al. Cyclosporine promotes the binding of the glomerular endothelium in vro, J Am Soc Nephrol, 1.1253 (1991), Bloom I T. et al. The aggravated renal vasoconstriction caused by cyclosporine is ^ mediated by endothelin-1 (ungía, 114480 (1993)) that caused vasoconstriction > ^ renal (Kon V and Avvazu M e i otocy of endothelin and cyclosporine. Renal Fall., 14: 345 (1992), Brooks DP et al Effect of nifedipm on cyclosporin-induced nephrotoxicity A. urinary endothelin excretion and number of renal endothelin receptors, in r .1 Phaimacol 194115 (1991) This acute CsA toxicity was suppressed with BQ123 in an atazana model (Fogo A, et al., Antagonism for the endothelin receptor is protective in the toxicity of acute ciclosporum in vivo, Kidney Int., 42: 770 (1992)). BQ123 (iv) predicts mitochondrial accumulation (Ca "") in the early phase of ischemic acute renal failure in rats and piotege the tubular cells close to the post ischemic degeneration that suggests possible endothelin inv investment. Pathogenesis of tubular lesions in the model of acute ischemic renal failure ßMino N, et al. Pi otcti effect of an endothelin selective receptor antagonist, BQ-123, in acute renal ischemic failure in rats. Eur J Pharmacol, 221 77 (1992)) The multi- ple administration of FR 139 ^ 1 7 in rats induced reduced abnormal permeability for proteins and limited glomerular lesions and prevented the deterioration of renal functions. The intracisternal ablation of FR 1393 17 significantly reduced the vasoconstriction of the basilar artery. .ai in the hemorrhage model l? Canine isubaracnoid (Nn ei II et al) An endothelin receptor antagonist ETA FR 139317 ameliorates cei ebral vasospasm in dogs Li e.Sci. 52 1869 (1993)) ET-1 induced arrhythmia in rats (Sogabe K, et al, Pharmacological profile of FR 139317, a new, potent endothelin antagonist ET-, .1 Pharmacol Exp Ther, 264: 1040 (1993)) was also suppressed by FR 1393 17 15 Nonselective antagonists of ETA / ETK such as PD 145065 and PD 142893 antagonized both impulse and depressant responses induced by ET-1 in a dose-dependent manner in anesthetized blocked ganglionic tatas (Doherty AM, et al., In vivo and in vitro studies with a series of hexapeptide endothelin antagonists, J. 0 Cardiovasc. Pharmacol. 1993 in print) The reductions induced by ET-1 in the renal flow in anesthetized rats (\ elling RP et al, The endosin-1-induced rats' kidney constriction is blocked by PD 14506"Third International Conference about Endothelin, Houston, February 15-17, 19 >; "Abstract 139) were completely inhibited by the previous administration of PD 145065 In anesthetized guinea pigs the PD 14 6 ^ M which increased the induced pulmonary inflation rate. by ET-I (Warner T D et il Inhibition by an endothene receptor antagonist not BRelective of bronchoconstuccinations induced by endoteima- 1 or sarafotoxin 6c in pig of guinea pig anesthetized Bi I 1'ha? macol impi enta) TI Ro 26-2005 demonstrated an effect protector for the vasoconstrictor, a? al after renal ischemia in anesthetized rats and It also reduced the metabolism of cei ebial vasoconstriction after hemorrhage. subarachnoid in rats Ro 46-2005 administered orally showed an effect antihypertensive with a reasonably long din (Clozel M, et al The discovery of Ro 46-2005 an antagonist n peptide available orally for the receptors of and ETB, third Symposium I your national on Endotelma Houston Texas February 1993, Clozel M, et ai Pathophysiological role of endothelin revealed by ppmer antagonist of the endothelial receptor active or oral nature 365 759 (1993)) The Ro 47-0203 was electiv or i model of subarachnoid hemon in rabbits for reverse vasoconstriction indicating that this compound crosses the blood barrier cerebral (Roux S P et al R? J "'- 203, a new endothelin receptor antagonist reverses the cystic vasospasm in experimental subaiacnoid hemorrhages, Circulation, Supplement) 1- 1 70 (1 991)) It is reported that Ro 47-0203 is in testing Early Clinical Paw S Al l c hypertension (Roux S P et al, Ro 47-0203, a new Ophthalmic receptor antagonist reverses chronic vasospasm in experimental hemorrhages or subarachnoids (p uilaeion 4 (part 2, Supplement) 1- 170 (1993)) Table I Tontomi ations of plasma ET-1 in humans Condition Control Normal Reported levels of ET plasma (pg / mL) Artenosclerosis 1 4 3 2 pmol / L Surgical operation 1 7 3 Buergei's disease 1 6 -i S Taka arteritis asu 1 6 Cardiogenic attack 0 3 3 7 '^ jFalla congestive of the Coi. izon 9 7 20 4 ÍCHF) 7 1 1 1 1 ^ Light CHF 7 I 1 3 8 Severe CHF 1 6 7 1 Cardio iopathy Dilated 10 4 j pmol / L 22 6 pmol / L Preclamsia 1 45 3 5 Pulmonary hypertension 1 5 Infarction acute myocardium 6 0 1 1 0 (Various Reports) 0 76 4 95? 50 3 8 0 4 Subarachnoid hemorrhage 0-24 fmol / mg 4-64 fmol / mg Crohn's disease 0-24 fmol / mg 20-50 fmol / mg Ulcerative colitis 1 2 S 4 ^ Cold pressure test 1 7 5 3 m "Raynaud's Phenomenon 2 8 5 0 ^ Cold hands of Ravnaud 7 10 9 Hernodialisis 1 88 4 59 (Several Reports) 1 88 1 1 Chronic renal failure 1 5 10 4 Acute renal failure 0 96 1 49 Hemodialysis before Ui emi 0 96 2 1 Hemodialysis postepoi a L l emí 1 8 5 33 9 Essential hypertension (1 1 9 9 Sepsis syndrome 6 1 1 1 9 Postoperative heart 1 5 4 2 Inflammatory arthritis 4 3 (after 1 6 2 malignant and emotional hemangioendothelioma) Rovero O et al. English Journal of Pharmacology. 101-232-236 (1990) present several analogs of the theoretical hexapeptide X of ET-l none of which was reported as an ET-1 antagonist.

Dohert A \ l. et al Abstract, Second Confei gum International on Endothelin, Tsukuba. Japan December 9, 1990, and the published manuscript (J. Cardiovasc.

Pharm, 17 (supplement "p l-Ñ'l (1991), present analogous vanes of the C-terminal hexapeptide of ET-! None of which exhibited ninuura functional activity.

The patent application ui joined states Copendent serial number 07 / 995,480 5 presents a series of novel endotehne antagonists However, we have praised the fact that a series of tetrapeptide hexapeptides and ETL-labeled logos are antagonists of the endothelin receptor. Additional data on the activity of peptides are found in the following references (( odv VVL, et al, J Med Chem 353301-3303 (1992), LaDouceurD M et al I \ Si I. (1 ^ .2)) Sl MARIO OF THE INVENTION According to the antenoi, the invention is a compound of Formula I AA'-AA -A '-AA AA'-AA6 I Number of ID of Seq 1 0 wherein R is hydrogen alkyl, alkenyl alkynyl cycloalkyl. cycloalkylalkyl. aryl, arylalkyl, 5-heteroaryl, fluorenylmethyl.

-N-R ¿3 where R ~ and R "are each the same or different v each one is l (ßT hydrogen. * Alkyl. alkenyl. alkynyl. cycloalkyl. -cycloalkylalkyl, t aryl, heteroaryl. fluorenylmethyl. O 0 -C I-IOR. , wherein R is as defined above, -OR2, wherein R2 is as defined above, OR -N- ICI-N-R, ", where R" and R are as defined R2 R "above.

OR -C-C (R9) 5, where R "is I (i Bi or I. where R ~ is as defined above, OR -N-C-R \ where R ~ is hydrogen or alkyl R 2A and R 'is as defined above, OR -N-C-OR '\ where R2 v R are as defined I R2"^ above excluvendt R is hydrogen or , where R2 is as defined above, R1 is hydrogen or alkyl.

Z is -OR-. fifteen - . 15 -S (0) "?. where neither is cei or an integer or 1 or 2.

-N-, where R "is as defined above # R2 - (CH2) "-, where n is zero or an integer of 1, 2. 3 or 4.

- (CH2) "- CH = CH- (CH,. -. Where n and n 'are each independently 0 equal or different and each as defined above pai a n, OR II -c-, -CR -. where R v R "are as defined I OR2 above or R- -C-. where R "and R are each the same or different -R 'and each is as defined above.

X and Y are equal and substituted c-n the same position soiire the aromatic chain and each can be 1. 2. 3 or 4 substitutes chosen from the group consisting of hydrogen, halogen, I rent, -CO2R-. where R "is as defined before. -CONR". where R "v R 'are as defined R 'u riba.

-MR, where R "v R 'are co or defined R 'up or nitro where R. Z X and Y are as defined above.

AA 'is Rx O -a - C C- R1 (CH2). wherein R "is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, -NR-, i, wherein RJ1 and R'h are each the same or R2b or different and each is hydrogen, alkyl. cycloalkyl, apl or heteroaryl.

-OR2. where R ~ is as defined above OR, -C-N R '". where R" 1 and R "are each equal and each is R "1 as defined above for R 2b and R" 3b where R h is as defined above or O -C-OR "'. where R is as defined above v R v n are as defined above or O R ' R is hydrogen, alkyl. 15 apl heteroai il. ^ O C-N'-R ''. wherein R2b and R, b are each R equal or different and each is as defined above, OR C -R where R is as defined above or it is as defined above and R 'and r. they are as defined above or AA is absent; you or each one is independently wherein R ° is hydrogen, alkyl, alkenyl, alkyl. ai il or heteroaril and R'yn are as defined above, wherein R is aryl or heteioaiyl Rs is O -C H-OR, where R is as defined above.

-OR1, where R1 is as defined above.

N-R1, wherein R1 is as defined R 'above or 5 -CH2-OR1, wherein R1 is as defined above and R' and n are as defined above; The stereochemistry in C in AA1-AA2-AA3-AA or-AA5 is D, L or DL and the stereochemistry in C in AAf > cs L, or a pharmaceutically acceptable salt thereof.

High levels of endothelin have been postulated to be included in a number of pathophysiological states including diseases associated with the cardiovascular system as well as various metabolic and endocrine disorders. As antagonists of endothelin, the compounds of F01 mule I are useful in the treatment of hypertension, myocardial infarctions, metabolic, endocrinological and neurological disorders, especially cerebral vasospasms, attacks and head injuries, congestive failures at rhythms, asthma and chronic and acute renal failure, pi eclamsia, atherosclerotic disorders including Raynaud's disease, restenosis, angina, cancer, pulmonary hypertension, ischemic diseases, gastric mucosal damage, hemorrhagic attacks, ischemic disease of the intestines and diabetes.

»Still another example of the present invention is a pharmaceutical composition I in dosage form Finally, the present invention is directed to methods for the production of a compound of Formula I DETAILED DESCRIPTION OF THE INVENTION s In the compounds of Formula I, the term "alkyl" means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl and the like The term "alkenyl" means a straight or branched unsaturated hydrocarbon radical having from 2 to 12 carbon atoms and includes, for example, ethenyl, 2-ijSropenil, 1-butenyl, 2-butenyl, 1-pentenyl, 2- pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, 1-octenyl, l-nenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl and the like.

The term "alkynyl" means an unsaturated hydrocarbon radical of straight or branched triple bond having from 2 to 12 carbon atoms and includes, for example, ethinyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 3-pentynyl, I-hexyl, l-octinyl, 2-octynyl, 1-noninyl, 2-noninyl, 3-noninyl, 4-noninyl, 1-decinyl, 2-undecinyl, 3-undecinyl, 3-dodecinyl and the like.

The term "cycloalkyl" means a saturated hydrocarbon chain containing, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.

The term "cycloalkylalkyl" means a saturated hydrocarbon chain attached to an alkyl group wherein alkyl is as defined above. The saturated hydrocarbon chain contains from 3 to 12 carbon atoms. Examples of the foregoing are cyclopropylmethyl, cyclopentiimethyl, cyclohexylmethyl, adamantylmethyl and the like , # ^ The term "alkoxy" and "lioalkoxy" are O-alkyl or S-alkyl as defined above.

The term "aryl" means an aromatic radical that is a phenyl group, a benzyl group, a naphthyl group, a biphenyl group, a pyrenyl group, an anthracenyl group, 3, 3-diphenylanyl, 10, II, - dihydro- 5H- dibenzo [a, dj- (cyclohepten-5-yl) glycyl or a fluorenyl group and the like, unsubstituted or substituted by from 1 to 4 substituted alkyl substitutes hydroxy, thiol, niti or, halogen, amino, NH-C I -alkyl wherein alkyl is as defined above, OO-DC-O-alkyl wherein alkyl is as defined arr-aba, -nC-alk. wherein alkyl is as defined above or aryl The term "arylalkyl" means an aromatic radical appended to an alkyl radical on trifluoryl and alkyl are as defined above, for example, benzyl, fluorenylmethyl and the like.

# The term "heteroaryl" means a heteroaromatic radical that is -2 or -3-thienyl, 2- or 3-furanyl, 2- or 3-pi? Otyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1 , 2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridinyl, 3-, 4- or 5-pyridazinyl, 2-pyrazinyl, 2-, 4 - or 5-pyrimidinyl, 2-, 3-, 4-, 5-, or-, 7- or 8-qu? nolinyl, 1 -, 3-, 4-, 5-, 6-, 7 or d-isoquinolinyl , 2-, 3-, 4-, 5-, 6- or 7- jenzo [b] thienyl or 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6 - or 7-benzothiazolyl, substituted or 2 substituted alkyl substitutes as defined above, aryl as defined above, alkoxy as defined above, thiozlkoxy co or defined above, hydroxy, thiol O nitro, halogen, formyl, amino, -NH-C 11-alkyl wherein alkyl is as defined above or O-JCJ-O-aallqquuiilloo eenn ddoonnddee aallqquuiilloo eess ccoommoo ssee ddeeffiinnee aarrriri .bbaa ,, --CC11-alq uilo wherein alkyl is as defined above or phenyl.

The term "heterocycloalkyl" means 2- or 3-tetrahydrothien, 2- or 3-tetrahydrofuran, 2- or 3-pyrrolidino, 2-, 4- or 5-thiazolidine, 2-, 4- or 5-oxazolidino, 2-, 3- or 4- piperidino, N-morpholinyl or N-thiamorpholinyl.

"Halogen" is lucent, chlorine, bromine or iodine.

The following table provides a list of the abbreviations and definitions of the used in the present invention. Abbreviation * Amino acid Ala Alanine Arg Arginine Asn Asparagine Asp Aspartic Acid Cis Cysteine Glu Glutamic Acid Gln Glutamine Glycine Glycine His Histidine He Isoleucine Leu Leucine Lis Lysine Met Methionine Phe (Fe) Phenylalanine Pro Proline Ser Serine Thr Threonine Trp Tryptophan Ti-Tyrosine Val Valine reviatura * Amino acid mod Bhí? 10, 11- Dihydro-5H-dibenzo [a, d] - (cycloepten-5-yl) glycine or • a-Amino-10, 11-dihydro-5H-dibenzo- [a, dJ cycloheptene-5-arnino acid Bip (Para-phenyl) phenylalanine * If the optical activity of the amino acid is different from L (S), the amino acid or abbreviation is preceded by the appropriate configuration D (R) or DL (RS) ABBREVIATION * Amino acid modified and unusual (cont.) Dip 3, 3- Diphenylalanine 3Hip 3- Hydroxyproline 4Hip 4 - Hydroxyproline N-Mefe N-Methylphenylalanine N-MeAs? N-Methylespartic Acid N-Melle N Methyl Isoleucine N-MeVal N-Methylvaline Nva Norvaline NIe Norleucine Orn Ornithine Abu-2-Aminobutyric Acid 2-Amino-4-Pentenoic Acid (Allyglycine) Arg (NO2) N ('-nitroarginine Atm 2-amino-3- (a-amino-5-thiazole) propane Cpn 2-amino-3-cyclopropanepropanoic acid (Cyclopropylalanine) Chx Cyclohexylalanine (Hexahydropentalalanine) N-MeChx N-methylcyclohexylalanine (N-Methylhexahydrophenylalanine) Emg Acid 2- amino-4, 5 (RS) - epoxy-4- pentenoic His (Dnp) Nin'- 2, 4- Dinitrophenylhistidine HomoGlu 2-Aminoadipic acid Homo Fe 2-amino-5-phenylpentanoic acid (Homophenylalanine) Met (O) Sulfoxide Methionine Met (O2) Sulfone Methionine I -Nal 3- (1'-naphthyl) alanine 2- to 3- (21-naphthyl) alanine Nia 2-amino-3-cyanopropanoic acid Pgl (cyanoalamine) Pgy Phenylglycine Fa 2-aminopentanoic acid (Propylglycine) Pyr 2-amino-6- (1-pyrol) -hexanoic acid 2-amino-3-acid - (3-pyridyl) -propanoic Tic (3- Pyridylalanine) Acid I, 2, 3, 4- Teli ahydro- 3- Tza isoquininalcarboxylic Tir (Ot-BU) 2- Amino-3- (4-thiazolyl) -propanoic acid Tir (OMe) O-tertiary butyl-tyrosine Ti (OEt) O-methyl tyrosine Trp (For) O-ethyl tyrosine Bheg N "1- Formyl-lriptofan Txg 5H-Dibenzo [a, dJ cycloheptene glycine Oxn 9H- Thioxanthene Glycine H- Xanthene Glycine ABBREVIATION * Protective Ac Acyl Acetate I - Adaptive Adamantyl Adoc Adamanyloxycarbonyl MeBzl 4- Mctylbenzyl z Benzyloxycarbonyl 2-Br-Z ortho-Bromobenzyloxycarbonyl 2-CÍ-Z ortho-chlorobenzyloxycarbonyl Bom Benzyloxymethyl Boc tertiary butyloxycarbonyl TBS tertiary butyldimethylsilyl Dnp 2, 4- Dinitrophenyl For Formil Fmoc 9-Fluorenylmethyloxycarbonyl NO2 Nitro Tos 4- Toluenesulfonyl (tosyl) Trt Trifenylmethyl (trityl) Ada I-adamantyl acetic acid Bz Benzylcarbonyl tBu t-Butylcarbonyl CF.CO Tritluoroacetyl Cxy Cyclohexylacetyl Et Cyclohexylurea Pia Propionyl Me (U) 3-pyridylacetyl Met i lurea * -If the optical activity of the amino acid is different from L (S), the amino acid or abbreviation is preceded by the appropriate configuration D (R) or DL (RS) ABBREVIATION Solvents and Reagents HOAc acetic acid CH., CN and ACN Accloniti ilo DCM Dichloromethane DCC N, N'- Dicyclohexylcarbodiimide DIEA N, N'- Diisopropylethylamine DMF Dimethylformamide HCl Hydrochloric acid HF Hydrochloric acid HOBt I - Hydroxybenzyltriazole KOH Potassium hydroxide TFA Trifluoroacetic acid Resin MBHA Resin methylbenzylhydrylamine Resin PAM Resin 4- (Oxymethyl) -phenylacetamidomethyl »The compounds of Formula I are capable of forming, in addition, both salts of Acidic or pharmaceutically acceptable base. All these forms are within the scope of the present invention.

The pharmaceutically acceptable acid addition salts of the compounds of the Formula I include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydrolytic, hydrofluoric, phosphorous and the like, as well as salts derived from non-toxic organic acids, such as acids by phenyl, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sullonic acids, etc. These salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, ato, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phenylacetate, citrate, lactate, maleate, jrtrate, methanesulfonary and the like Also contemplated are salts of amino acids such as arginate and the like and glutaconate, galacturonate ( See, for example, Berge SM, et al, "Sales Fai Maceutics" Journal of Science Pharmaceutical, 66 1-19 (1977)).

The acid addition salts of said basic compounds are piperated upon contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner. Preferably a peptide of Formula I can be converted to an acidic salt. treating it with an aqueous solution of the desired acid, so that the resulting pH is less than 4 The solution can be passed to you birds of a C18 # cartridge to absorb the peptide, wash with copious amounts of water, elute the peptide with a polar organic solvent such as, for example, methanol, acetonitrile, aqueous mixtures of the # and similar and isolate by concentrating under reduced pressure after lyophilization. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in polar solvents, but otherwise the salts are equivalent to their respective free base for the purposes of the present invention. v The pharmaceutically acceptable basic addition salts are formed with metals or amines, such as the alkali and alkali earth metals or organic amines. Examples of the metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (See, for example, Berge SM, et al., "Pharmaceutical Sales", Journal of Pharmaceutical Science, 66: 1-19 The basic addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner, preferably, a peptide of Formula I can be converted to a base addition salt when treated with an aqueous solution of the desired base, so that the resulting pH is greater than 9. The solution can be passed through an IC 8 cartridge to absorb the peptide, washed with copious amounts of water , eluting the peptide with a polar organic solvent such as, for example, methanol. acetonitrile, aqueous mixtures thereof and the like and isolating it by concentrating under reduced pressure after lyophilization The free-released form can be regenerated by contacting the # Saline with an acid and isolating the acid form in the conventional way. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their free acid form for the purposes of the present invention.

Certain compounds of the present invention can exist in non-solubilized forms as well as solubilized forms, including hydrated forms. In general, the solubilized forms, including the hydrated forms, are equivalent to the insolubilized forms and are intended to be within the scope of the present invention.

Certain compounds of the present invention possess one or more chiral centers and each center may exist in the configuration R (D) or S (L). The present invention includes all the enantioletric and epimeric Kbrmas as well as the appropriate mixtures thereof.

A favorite issue of Formula I is one where AA1 is wherein R is -N-R2 R- wherein R2 and 1 are each the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl aryl, arylalkyl heteroapl, fluoienylmethyl, O-N-C il-N-R 3, wherein R and R 1 are as defined R ai nba. OR J- -CC ((RR99) k3, where Rt.} Is F, Cl, Bi or I, O -NH-C-R3, where lβ is as defined above or where IV is as defined above excluding R is hydrogen, Z is - O-, -) "" where neither is zero or an integer or 1 or 2, where R is as defined above - (CH2) "-, where n is zero or an integer of 1, 2 , 3 or 4, - (CH2) "- CH: = CH- (CH2)" -, where n and n 'are each independently the same or different and each as defined above for n, -CH-, wherein R1 is hydrogen or alkyl OR1 R¿ -C I-, where R and R are each equal or different I -R3 and each is as defined above and ¿L and Y are equal and substituted in the same position on the aiomatic chain and each substitute is choose from the group consisting of hydrogen, halogen or alkyl, AA2 is where R is hydrogen. alkyl, alkyl, alkynyl, cycloalkyl, aryl, heteioapl, -N-IV. wherein R2h and R3'1 are each the same or R21 'or different and each is hydrogen, alkyl, cycloalkyl, anl or hetei oanl, -OR21', wherein R2b is as defined above wherein R h is as defined above where R, 2 'and, R, li' are each the same or different and each is as defined above for R I > and R b, R ', where R, 2b' is as defined above H-R, 2b wherein R 2b 'is as defined above or O II -C-OR21 ', where R2h is as defined above and R1 and n are as defined above or AA2 is absent, or? V where W is - ICI- or -C- R5 is aril. heteroai íl, wherein R2b and R3b are each the same or different and each is as defined above, OR C II-R ', where R, 2b' is as defined ai i went o C l? -OR "'. Where R' is as defined above and R and n are as defined above or AA is absent.

JSP and AA are each independently absent or each is independently wherein R 6 is hydrogen, alkyl, 10 9 ™ alkenyl, alkynyl. hetei oai il and R1 and n are as defined above; fifteen 0 where R is ai il or hetei oai il and R1 and n are as defined above or O - C * H-C l N-R1 where R, 7, R and n are as defined above, The stereochemistry in C in AA1-AA2-AA3-AA or-AA5 is D, L or DL and the stereochemistry in C in AA ° is L, or a pharmaceutically acceptable salt thereof.

A most favorite compound of Formula I is one where AA is where R is wherein K2 and R3 are each the same or different and each is hydrogen, alkyl, ai or fluorenylmethyl, O • NC ??-N-R3, where R "and R are as defined cn where R9 is F, Cl, Br or I, where R "is as defined above or Or -NH-C11-OR1", wherein RH1 is hydrogen, alkyl, aryl, arylalkyl or tluoi enylmethyl, excluding R1" is hydrogen, Z is -O-, -S- -NH-, - (CHj) ,, -, where n is zero or an integer of 1, 2, 3 or 4 or - (CI L) ,,, -CI L CI I- (CI L) ", -? -, where na and n" 1 are each way Independent W equal or different and each is zero or an integer of 1 or 2 and X and Y are the same and substituted in the same position on the aromatic chain and each substitute is selected from the group consisting of hydrogen, halogen or alkyl, A is or II 9L: HC-, R (CH2) n R4 wherein R1 is hydrogen or methyl, R4 is alkyl, aryl, heteroaryl, § ^ -NR "", wherein R21 'and IV1' are each one equal or | R2b or different and each is hydrogen or alkyl, Or -C-N-R31 ', wherein R21' and IV1 'are each the same and each is hydrogen or alkyl, 2b or II -C-R21 ', wherein R21' is as defined above NH-NH-1C-NH-R 2b ', wherein R' is as defined arpba or O -C-OR21 ', where R2b is as defined above and n is zero or an integer of 1, 2, 3 or 4 or AA2 is absent, AA3 is O R 'where W is -C- or -C-, R1 R' is ai 11 oai il HIV, wherein R is hydrogen or alkyl, O -C-R21 ', wherein R2b is hydrogen or alkyl or O -C-OR21', wherein R2b is hydrogen or alkyl and R1 and n are as defined above,% AA and AA are each independently where IV is Indigenous, alkyl, l R1 and n are as defined above; AAb is wherein R7 is aryl or heteroaryl and R1 and n are as defined above or % where R7, R1, R1 and n are as defined above.

The stereochemistry in C in AA1- AA2- AA3- A.Vo- AA5 is D, L or DL and the * stereochemistry in C in AA "is L, or a pharmaceutically acceptable salt thereof.

They are particularly valuable L-Bhg-Leu-Asp-lie-lie-Trp; Seq ID No: 2 D-Bhg-Leu-Asp-lie-lie-Trp; Seq ID No: 2 Ac-L-Bhg-Le -Asp-liele-Trp; Seq ID No: 2 Ac-D-Bhg-Leu-Asp-Ile-Ile-Trp; Seq ID No: 2 Ac-D-Bhg-Orn-sp lie-lie-Trp; Seq ID No: 3 Ac-D-Bhg-Lys-Asp-lie-lie-Trp; Seq ID No: 4 Ac-D-Bhg-Asp-Asp-Ile-Ile-Trp; Seq ID No: 5 Ac-D-Bhg-Glu-Asp-Ile-Ile-Trp; Seq ID No: 6 Ac-D-Bhg-Phe-Asp-lie-Ile-Trp; Seq ID No: 7 Ac-D-Bhg-Arc? -As? -Ii.e-He-Trp; Seq ID No: 8 ß.c-D-Bhg-JVtp-Ile-11-e-T? .- p; Seq ID No: 9"Íímoc-D-Bhci-e'u-Asp Tle.jie-Trp; Seq ID No: 2 Fmoc-D-Bhci-Om-Asp-Ile-He-Trp; Seq ID No: 3 Fmoc-D-Bhcf: Lys-Asptele.ne-Trp; 'Seq ID No:? Fmoc-D-Bhg- sp- lie-Ile-Trp; Seq ID No: 5 Fmoc-D-Bhg-Glu-Asp- lie- Ile -Trp; Seq ID NO: fi Fmoc-D-Bhg-Phe-sp lie-Ile-Trp; Seq ID No: 7 Fmoc-D-Bhg-Ar -Asp- lie-lie-Trp; Seq ID No: S Fmoc-D-Bhg- sp lie-lie-Trp; Seq ID No: O and cD-Bhg-Leu-Pheillee-Trp; Seq ID No: 10 Me -D-Bhg-T.eu.- Asp -13 ß- 11e-Trp; Seq ID No: 1! Ac-D-Bhg -teu-Cln -Ile-Ile-Trp; Seq ID No: 12? C -D-Bhg - eu-Cin-ILe-Ile -Trp; Seq ID Nu: 1 Ac-D-Bh < j-'Ueu-Tyr-Ile-IlG-Trp; Seq ID No- J4? CD-Bhg-Leu 1-Nal -He- He-Trp; Seq ID No: L5? CP-Bnq-L u-2-Na. -Ile-Ile-Trp; Seq ID No- I b Ac-D-Bhg-Leu-Trp-Ile-Ile-Trp; Seq ID N, or: 16 Ac-D-Bhg-Leu-Asp-Val -lie-Trp; Seq lüo: 17 Ac-D-Bhg-Leu-Aspr He-Val -Trp; Seq ID No: 18 Ac-D-Bhg-Leu-Asp-Chichel-Trp; Seq ID No: 19 Ac-D-Bhg-Leu-Asp-lie-Chx-Trp; Seq ID No: 20 Ac-D-Bhg-Arg-Asp-He-Chx-Trp; Seq ID No: 21 Ac-D-Bhg-Lys -Asp-lie-Chx-Trp; Seq ID No: 22 Ac-D-Bhg-Orn-Asp-He-Chx-Trp; Seq ID No: 23 Ac-D-Bhg-? Sp-Asp- He-Chx-Trp; Seq ID No: 24 Ac-D-Dhg-Glu-Asp-Ile-Chx-Trp; Seq ID No: 25 Fmoc -D-Bhg-Leu-Phe-He-He-Trp; Seq ID No: 10 Fiuoc-D-Bhg-Leu-Asn-Ile-Ile-Trp; Seq ID No: 11 Seq ID No: 12 Seq ID No: 13 Seq ID No: 14 Finoc- -Bhg- Leu-Asp-Val-He-Trp; Seq ID No: 17 Fmoc -1) - Bhg - Leu-Asp-He-Val -Trp; Seq ID No: 18 Fmoc-D-Bhg-Leu-Asp-Chx-He-Trp; Seq ID No: 19 Fmoc-D-Bhg -Arg-Asp- Chx-lie-Trp; Seq ID No: 26 Fxnoc-D-Bhg-Lys-Asp-Chx-lie-Trp; Seq ID No: 27 Fmoc-D-Bhg-Orn-Asp-Chx-He-Trp; Seq ID No: 28 Fmoc -D-Bhg-Asp-Asp-Chx-He-Trp; Seq ID No: 29 Fmoc-D-Bhg-Glu-Asp-Chx-He-Trp; Seq ID No: 30 moc-D-Bhg -Leu-Asp- He-Chx-Trp; Seq ID No: 20 % Fmoc-D-Bhg -Arg-Asp-lie-Chx-Trp; Seq ID No: 21 Fmoc-D-Bhg-Lys-Asp-He-Chx-Trp; Seq ID No: 22 Fmoc-D-Bhg-Orn-Asp-He-Chx-Trp; Seq ID No: 23 Fmoc-D-Bhg-Asp-Asp-lie-Chx-Trp; Seq ID No: 24 Fmoc-D-Bhg-Glu-Asp-He-Chx-Trp; Seq ID No: 25 Ac-D-Bheg-Leu-Asp-He-Ile-Trp; ? cq ID No 2 Ac-D-Bheg-Orn-Asp-Ile-Ile-Trp; Seq ID No 3? C-D- hc - ys-? S - II .. - -. - rp; Seq ID No 4 A.c-D-Bheg-Asp-Asp-Ile-He-Trp; Seq ID No 5? C-D-l.hog-Glu-? Sp-Ile-lle-Trp; Seq ID No 6? C -D- Bhcg-Phe-Ac -lie -lie-Trp; Srq ID No 7? C-Ü-Dheg-? Rg-Asp-Ile-Ile-Trp; Seq ID No 8? C-D-Dhcg-? Sp-Ile-llc-Trp; S-a ID No 9 Fmoc-D-Bheg-Leu-Asp-lie-lie-Tzp; Seq ID or :: 2 Fmoc-D-Bheg-Orn-Asp-Ile lle-Trp; Seq ID: 3 Fmoc-D-Bheg-Lys-Asp-lie-lie-Trp; Seq ID: 4 Fmoc-D-Bheg-Asp-Asp-Ile-Ile-Trp; Seq ID: 5 Fmoc-D-Bheg-Glu-Asp-Ile-Ile-Trp; Seq ID: 6 Fmoc-D-Bheg-Phe-Asp-Ile-Ile-Trp; Seq ID: 7 Fmoc-D-Bheg-Arg-Asp-Ile-Ile-Trp; Seq ID: 8 Fmoc-D-Bheg-Asp-lie-lie-Trp; Seq ID: 9 Ac-D-Bheg-Leu-Phe-Ile-Ile-Trp; Seq ID: 10 Ac-D-Bheg-Leu-Asn-lie-lie-Trp; Seq ID: 11 Ac-D-Bheg-Leu-Glu-ie-lie-Trp; Seq ID: 12 Ac-D-Bheg-Leu-Gln-lie-lie-Trp; Seq ID: 13 Ac-D-Bheg-Leu-Tyr-lie-lie-Trp; Seq ID: 14 Ac-D-Bheg-Leu-1-Nal-Ile-Ile-Trp; Seq ID: 15 Ac-D-Bheg-Leu-2-? Al-Ile-Ile-Trp; Seq ID: 15 Ac-D-Bheg-Leu-Trp-Ile-He-Trp; Seq. ID: 16 Ac-D-Bheg-Leu-Asp-Val-lie-Trp; Seq ID: 17 Ac-D-Bheg-Leu-Asp-Ile-Val-Trp; Seq ID: 18 Ac-D-Bheg-Leu-Asp-Chx-He-Trp; Seq ID: 19 Ac-D-Bheg-Leu-Asp-lie-Chx-Trp; Seq ID: 20 Ac-D-Bheg-Arg-Asp-He-Chx-Trp; Seq ID: 21 Ac-D-Bheg-Lys-Asp-lie-Chx-Trp; Seq ID: 22 Ac-D-Bheg-Orn-Asp-lie-Chx-Trp; Seq ID: 23 _ Ac-D-Bheg-Asp-Asp-lie-Chx-Trp; Seq ID: 24 »Ac-D-Bheg-Glu-Asp-He-Chx-Trp; Seq. ID: 25 Fmsc-D-Bheg-Leu-Phe-He-Ile-Trp; Seq ID? O: 10 Fmoc-D-Bheg- eu-Asn-lie-lie-Trp; Seq. ID: 11 Fmoc-D-Bheg-Leu-Glu-Ile-Ile-Trp; Seq. ID: 12 Fmoc-D-Bheg-Leu-Gln-He-He-Trp; Seq ID: 13 Fmoc-D-Bheg-Leu-Tyr-He-He-Trp; Seq ID: 14 Fmoc-D-Bheg-Leu-Asp-Val-He-Trp; Seq ID: 17: Fxnoc-D-Bheg-Le -Asp-He-Val -Trp; Seq ID: Tea Fmoc-D-Bheg-Leu-Asp-Chx-He-Trp; Seq ID: 19 Fmoc-D-Bheg-Arg-Asp-Chx-He-Trp; Seq ID? O:? (- Fmoc-DB.ieg-Ly- -Asp-Chx-lie-Trp; Seq ID? O: y: Fmsc-D-Bheg-Orp-? Sp-Chx-He-Trp; Seq ID? O: 28 Fmoc-D ~ l.heg-A5-: -? Sp-Chx-lie-Trp; Seq ID? O: Fxnoc-D-Bheg-Glu-Asp-Chx-He-Trp; Seq 'ID No: 30 Fmoc-D-Bheg-Leu-Asp- He-Chx-Trp; Seq ID No: 20 Fmoc-D-Bheg-Arg-Asp-He-Chx-Trp; Seq ID No: 21 Fmoc-D-Bheg-Lys? Sp-lie-Chx-Trp; Seq ID No: 22 Fmoc-D-Bheg-Orn-Asp-lie-Chx-Trp; Seq ID No: 23 Fmoc-D-Bheg-Asp-? Sp-He-Chx-Trp; Seq ID No: 24 Fmoc-D-Bheg-Glu-Asp-liex-Trp; Seq ID No: 25 Ac-D-Tx -Leu-Asp-lie-lie-Trp; Seq ID No: 2 Ac-D-Txg-Orn-Asp-lie-Ile-Trp; Seq ID No: 3 Ac-D-Txg-Lys-Asp-He-He-Trp; Seq ID No: 4 Ac-D-Txg-? Sp-Asp-lie-lie-Trp; Seq ID No: 5 Ac-D-Txg-Glu-Asp-Ile-Ile-Trp; Seq ID No: 6? C-D-Txg-Phe-Asp-lie-Ile-Trp; Seq ID No: 7 Ac-D-Txg-Arg-Asp-Ile-Ile-Trp; Seq ID No: 8 Ac-D-Txg-Asp-lie-lie-Trp; Seq ID No: 9 Fmoc-D-Txg-Leu-Asp-lie-Ile-Trp; Seq ID No: 2 Fmoc-D-Txg-Orn-As? -Ile-Ile-Tr ?; Seq ID No: 3 • Fmac-D-Txg-Lys-Asp-lie-lie-Trp; Seq ID No: 4 Fmoc-D-Txg-Asp-Asp-He-He-Trp; Seq ID No: 5 Fmoc-D-Txg-Glu-Asp-He-He-Trp; Seq ID No: 6 Fmoc-D-Txg-Phe-Asp-lie-lie-Trp; Seq ID No: 7 Fmoc- -Txg-Arg-Asp- He-Ile-Trp; Seq ID No: 8 Fmoc-D-Txg-Asp-lie-lie-Trp; Seq ID No: 9 Ac-D-Txg-Leu-Phe-lie-lie-Trp; Seq ID No: 10 Ac-D-Txg-Leu-Asn-He-He-Trp; Seq ID No: 11 Ac-D-Txg-Leu-Glu lie-lie-Trp; Seq ID No: 12 Ac-D-Txg-Leu-Gln-Ile-Ile-Trp; Seq ID No: 13 Ac-D-Txg-Leu-Tyr-Ile-Ile-Trp; Seq ID No: 14 Ac-D-Txg-Leu-1-Nal-lie-Ile-Trp; Seq ID No: 15? C-D-Txg-Leu-2-Nal -lie-lie-Trp; Seq ID No: 15 Ac-D-Txg-Leu-Trp-lie-lie-Trp; Seq ID No: 16 Ac-D-T g-Leu-Asp-Val-Ile-Trp; Seq ID No: 17 Ac-D-Txg-Leu-sp-He-Val-Trp; Seq ID No: 18? C - D - T: g - Leu - Asp - Chx - He - Rp; Seq ID No: 19? C - D-T..g - Leu-Asp- He- Chx- Trp; S'.q ID No: 20? C - D- Txg -Arg -? Sp- 11e - Ciix- Trp; Seq ID No: 21? C - D Txg - l-ys -? - 1.1 c - Chx- Trp; ..- •• ID No: 22 Ac-D-Txg-Orn-Asp-He-Chx-Trp; Seq iD No: 23 Ac-D-Txg-Asp-Asp-He-Chx-Trp; Seq ID NO: 24 it Ac-D-Txg-Glu-Asp-Ile-Chx-Trp; seq ID NO: 25 Fmoc -D-Txg- Leu- Phe -He- He -Trp; seq ID O: 10 Fmoc-D-Txg-Leu-Asn-Ile-He-Trp; seq ID NO: 11 Fmoc-D-Txg-Leu-Glu-He-He-Trp; seq ID O: 12 Fmoc-D-Txg-Leu-Gln-He-He-Trp; seq ID O: 13 Fmoc-D-Txg-Leu-Tyr-Ile-He-Trp; seq ID NO: 14 Fmoc-D-Txg-Leu-Asp-Val-He-Trp; seq ID O: 17 Fmoc-D-Txg-Leu-Asp-He-Val-Trp; seq ID NO: 18 Fmoc -D-Txg -Leu- Asp- Chx- He -Trp; seq ID O: 19 Fmoc -D- Txg- Arg -Asp- Chx- Ile-Trp; seq ID NO: 26 Fmoc-D-Txg-Lys-Asp-Chx-He-Trp; seq ID NO: 27 Fmoc-D-Txg-Orn-Asp-Chx-He-Trp; Seq ID No: 28 Fmoc-D-Txg-Asp-Asp-Chx-Ile-Trp; Seq ID NO: 29 Fmoc-D-Txg-Glu-Asp-Chx-He-Trp; Seq ID NO: 30 Fmoc -D-Txg -Leu- Asp- He -Chx- Trp; : .eq ID O: 20 Fmoc -D-Txg-Arg-Asp- He-Chx-Trp; £ eq ID NO: 21 Fmoc-D-Txg-Lys-Asp-He-Chx-Trp; Seq ID O: 22 Fmoc-D-Txg-Orn-Asp-He-Chx-Trp; Saq ID NO: 23 Fmoc-D-Txg-Asp-Asp-He-Chx-Trp; s..q ID O: 24 Fmoc-D-Txg-Glu-Asp-He-Chx-Trp; Seq ID O: 25 Et-D-Bhg-Leu-Asp-He-Ile-Trp; Seq ID O: 2 Bz-D-Bhg-Leu-Asp-He-He-Trp; Seq ID NO: 2 Pya-D-Bhg-Leu-Asp-He-He-Trp; Seq ID NO: 2 Cxl-D-Bhg-Leu-Asp-He-He-Trp; seq ID NO: 2 Ada-D-Bhg-Leu-Asp-He-Ile-Trp; s ID NO: 2 Cxi (U) -D-Bhg-Leu-Asp-Ile-He-Trp; Seq ID NO: 2 Me (U) -D-Bhg-Leu-Asp-He-He-Trp; seq ID or: 2 tBu-D-Bhg-Leu-Asp-He-He-Trp; Seq ID NO: 2 CF3CO-D-Bhg-Leu-Asp-He-He-Trp; Seq ID NO: 2 ? t-D-Bheg-Leu-Asp-Ile-He-Trp; Seq ID O: 2 Bz-D-Bheg-Leu-Asp-He-He-Trp; Seq ID NO: 2 Pya-D-Bheq-Leu-sp-Ile-He-Trp; Seq ID O: 2 Cxl-D-Bheg-Leu-? Sp-Ile-He-Trp; i ID NO: 2 Ada-D-Bheg-Leu-Asp-He-He-Trp; Seq ID NO: 2 Cxi (U) -D-Bheg-Leu-Asp-He-He-Trp; Seq ID No: 2. e (U) -D-Bheg-Leu-Asp-Ile-Ile-Trp; Seq ID No 2 tBu-D-Bheg-Leu-Asp-lie-lie-Trp; Seq ID No 2 CF3CO-D-Bheg-Leu-Asp-lie-Ile-Trp; Seq ID No: 2 Ac-D-Bhg-Leu-Asp-Phe-He-Trp; Seq ID No: 31 'Ac-D-Bhg-Orn-Asp-Phele-Trp; Seq ID No: 32 c-D-Bhg-Lys -Asp-Phe-He-Trp; Seq ID No: 33 Ac-D-Bhg-Asp-Asp-Phe-lie-Trp; Seq ID No: 34 Ac-D-Bhg-Glu-Asp-Phe-He-Trp; Seq ID No: 35 Ac-D-Bhg-Phe-Asp-Phe-He-Trp; Seq ID No: 36 Ac-D-Bhg-Arg-Asp-Phe-He-Trp; Seq ID No: 37 Ac-D-Bheg-Leu-Asp-Phe-He-Trp; Seq ID No: 31 Ac-D-Bheg-Orn-Asp-Phe-Ile-Trp; Seq ID No: 32 Ac-D-Bheg-Lys-Asp-Phe-He-Trp; Seq ID No: 33 Ac-D-Bheg-Asp-Asp-Phe-lie-Trp; Seq ID No: 34 Ac-D-Bheg-Glu-Asp-Phe-Ile-Trp; Seq ID No: 35 Ac-D-Bheg-Phe-Asp-Phe-He-Trp; Seq ID No: 36 Ac-D-Bheg-Arg-Asp-Phe-lie-Trp; ' Seq ID No: 37 L-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 D-Bhg-Leu-Asp- He-N-Melle-Trp; Seq ID No: 20 Ac-L-Bhg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Ac-D-Bhg-Leu-Asp-lie-N-Melle-Trp; Seq ID No: 20 Ac-D-Bhg-Orn-Asp-He-N-Melle-Trp; Seq ID No: 38 Ac-D-Bhg-Lys-Asp-He-N-elle-Trp; Seq ID No: 22 Ac-D-Bhg-Asp-Asp-Ile-N-Melle-Trp; Seq ID No: 24 Ac-D-Bhg-Glu-Asp-He-N-Melle-Trp; . Seq ID No: 25 Ac-D-Bhg-Phe-Asp-He-N-elle-Trp; Seq ID No: 39 Ac-D-Bhg-Arg-Asp-He-N-Melle-Trp; Seq ID No: 21 Ac-D-Bh -Asp-lie-N-Melle-Trp; Seq ID No: 40 Fmoc-D-Bhg-Leu-Asp-Ile-N-elle-Trp; Seq ID No: 20 Fmoc-D-Bhg-Orn-Asp- He-N-Melle-Trp; Seq ID No: 38 Fmoc-D-Bhg-Lys-Asp-He-N-elle-Trp; Seq ID No: 22 Fiuoc-D-Dhg-? Sp-? Sp-Ile-N-Melle-Trp; Soq ID No: 24 Fmoc-D-Bhg-Glu-? Sp-He-N-Melle-Trp; Seq ID No: 25 Fpioc - D - Bhg - Phe -? Sp - He - N - Melle - Trp; Seq ID No: 39 Fmoc - D - Dhg - Arg -? Sp - Ile - N - Melle - Trp; Seq ID No: 21 F oc -D - Bhg -? Sp - He - N-Melle-Trp; on ID No: 40 c - D - Bhg - Leu - Phe - He - N - Melle -Trp; . *. < "" -1 ID No: 41 Ac-D-Bhg-Leu-Asn-Ile-N-Melle-Trp; Seq ID: 20 Ac-D-Bhg-Leu-Glu-He-N-elle-Trp; Seq ID: or: 42 ^^ Ac-D-Bhg-Leu-Gln-He-N-elle-Trp; Seq ID: 43 ^^ Ac-D-Bhg-Leu-Tyr-Ile-N-Melle-Trp; Seq ID: 44 Ac-D-Bhg-Leu-l-Nal-Ile-N-Melle-Trp; Seq ID: 45 Ac-D-Bhg-Leu-2-Nal-He-N-elle-Trp; Seq ID: 45 Ac-D-Bhg-Leu-Trp-He-N-Melle-Trp; Seq ID: 46 Ac-D-Bhg-Leu-Asp-Val-N-Melle-Trp; Seq ID: 47 Ac-D-Bhg-Leu-Asp-Ile-N-MeVal-Trp; Seq ID: 20 Ac-D-Bhg-Leu-Asp-Chx-N-Melle-Trp; Seq ID ?: 48 Ac-D-Bhg-Leu-Asp-Ile-N-MeChx-Trp; Seq ID: 20 Ac-D-Bhg-Arg-Asp-He-N-MeChx-Trp; Seq ID: 21 Ac-D-Bhg-Lys-Asp-He-N-MeChx-Trp; Seq ID: 22 Ac-D-Bhg-Orn-Asp-Ile-N-MeChx-Trp; Seq ID: 38 ^ Ac-D-Bhg-Asp-Asp-Ile-N-MeChx-Trp; Seq ID: 24 Ac-D-Bhg-Glu-Asp-He-N-MeChx-Trp; Seq ID: 25 Fmoc-D-Bhg-Leu-Phe-Ile-N-elle-Trp; Seq. ID: 41 Fmoc-D-Bhg-Leu-Asn-He-N-Melle-Trp; Seq ID: 20: Finoc-D-Bhg-Leu-Glu-Ile-N-Melle-Trp; Seq. ID: 42 Fmoc-D-Bhg-Leu-Gln-Ile-N-elle-Trp; Seq ID: 43 Fmoc-D-Bhg-Leu-yr-Ile-N-elle-Trp; Seq ID ?: 44 Fmoc-D-Bhg-Leu-Asp-Val-N-Melle-Trp; Seq ID: 47 Fmoc-D-Bhg-Leu-Asp-Ile-N- eVal-Trp; Seq ID: 20 5 ^ F sc-D-Bhg-Leu-Asp-Chx-N-Melle-Trp; Seq ID: 49 ^ Fmoc-D-Bhg-Arg-Asp-Chx-N-Melle-Trp; Seq ID: 50 Fmoc-D-Bhg-Lys-Asp-Chx-N-Melle-Trp; Seq ID ?: 51 Fmoc-D-Bhg-Orn-Asp-Chx-N-elle-Trp; Seq ID ?: 52 Fmoc-D-Bhg-Asp-Asp-Chx-N-Melle-Trp; Seq ID: 53 Fmoc-D-Bhg-Glu-Asp-Chx-N-Melle-Trp; Seq ID: 54 Fmoc-D-Bhg-Leu-Asp-He-N-MeChx-Trp; Seq ID: 20 Fmoc-D-Bhg-Arg-Asp-He-N-MeChx-Trp; Seq ID: 21 Fmoc-D-Bhg-Lys-Asp-He-N- eChx-Trp; Seq ID: 22 Fmoc-D-Bhg-Orn-Asp-He-N-MeChx-Trp; Seq ID: 38 Fmoc-D-Bhg-Asp-Asp-Ile-N-MeChx-Trp; Seq TD? O: 24 Fmoc-D-Bhg-Glu-Asp-He-N-MeChx-Trp; Scu ID o; 25 ? c-D-Bheg-Leu-? s -He -? - Melle-Tr, • Seq ID: 20? c-D-Bheg-Orn-? sp-Ile -? - Melle-Trp; Be ID? O: 30 Ac-D-Bheg -Lys -Asp- Ile-N-Melle-Trp; Seq ID No: 22 Ac -D-Bheg -Asp- Asp- lie -r- Melle -Trp; Seq ID No: 24 ? c -D- Bheg -Glu-Asp- Ile-N-Melle-Trp; Seq ID No: 25 * Ac-D-Bheg-Phe -Asp-Ile-N-Melle-Trp; Seq ID No: 39 Ac -D-Bheg-Arg-Asp-Ile-N-Melle-Trp; Seq ID No: 21 Fmoc -D-Bheg-Leu-D-Asp- He-N-MeIle-Trp; Seq ID No: 40 Fmoc-D-Bheg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Fmoc-D-Bheg-Orn-Asp-Ile-N-Melle-Trp; Seq ID No: 38 Fmoc -D-Bheg -Lys -Asp- He-N-Melle -Trp; Seq ID No: 22 Fmoc -D-Bheg -Asp- Asp- He-N-Mell -Trp; Seq ID No: 24 Fmoc -D-Bheg -Glu-? Sp- Ile-N-Melle -Trp; Seq ID No: 25 Fmoc-D-Bhe -Phe-Asp-Ile-N-Melle-Trp; Seq ID No: 39 Fmoc -D-Bheg -Arg -Asp- He-N-Melle -Trp; Seq ID No: 21 Fmoc -D-Bheg -Asp- lie -N-Melle- Trp; Seq ID No: 40 Ac-D-Bheg-Leu-Phe-lie-N-Mellere; Seq ID No: 41 Ac -D-Bheg -Leu -Asn-lie -N-Melle -Trp; Seq ID No: 55 Ac-D-Bheg-Leu-Glu-Ile-N-Melle-Trp; Seq ID No: 42 Ac-D-Bheg-Leu-Gln-Ile-N-Melle-Trp; Seq ID No: 43 'Ac-D-Bheg - Leu-Tyr-Ile- T. -Melle-Trp; Seq ID No: 44 Ac-D-Bheg-Leu-1-Nal-He-N-Melle -Trp; Seq ID No: 45 Ac -D-Bheg-Leu-2-Nal-He-N-Melle-Trp; Seq ID No: 45 Ac-D-Bheg-Leu-Trp-Ile-N-Melle-Trp; Seq ID No: 46 Ac-D-Bheg - Leu-Asp-Val-N-Melle -Trp; Seq ID No: 47 ? c -D-Bheg- Leu -Asp - He -N-Me Val -Trp; ? eq ID No: 20 Ac-D-Bheg-Leu-Asp-Chx-N-Melle-Trp; Seq ID No: 49 Ac-D-Bheg-Leu-Asp-Ile-N-MeChx-Trp; Seq ID No: 20 Ac-D-Bheg-Arg-Asp-He-N-MeChx-Trp; Seq ID No: 21 Ac-D-Bhe-Lys-Asp-Ile-N-MeChx-Trp; Seq ID No: 22 Ac-D-Bheg-Orn-Asp-He-N-MeChx-Trp; Seq ID No: 38 Ac-D-Bheg-Asp-Asp-lie-N-MeChx-Trp; Seq ID No: 24 c-D-Bheg-Glu-Asp-Ile-N-MeChx-Trp; Seq ID No: 25 Fmoc-D-Bheg-Leu-Phele-N-Melle-Trp; Seq ID No: 41 Fmoc-D-Bheg-Leu-Asn-He-N-Melle-Trp; Seq ID No: 55 Fmoc-D-Bheg-Leu-Glu -lie-N-Melle-Trp; S q ID No: 42 moc-D-Bheg -Leu-Gln- He-N-elle-Tr; Soq ID No: 43 Fmoc-D-Bhe -Leu-Tyr- II -. -N-Melle-Trp; Seq ID No: 44 Fmoc-D-Bheg-eu-? Ep-Val-N-Melle-Trp; 5 ^ -? ID No: 47 Fmoc-D-Bheg-Leu-Asp-lie-N-MeVal-Trp; Seq ID No: 20 Fmoc-D-Bheg-Leu-Asp-Chx-N-Melle-Trp; Seq ID No: 49 Fmoc-D-Bheg-Arg-Asp-Chx-N-Melle-Trp; Seq ID No: 50 L Fmoc-D-Bheg-Lys-Aep-Chx-N-Melle-Trp; Seq ID No: 51 Fmoc-D-Bheg-Orn-Asp-Chx-N-Melle-Trp; Seq ID No: 52 Fmoc-D-Bheg-Asp-Asp-Chx-N-Melle-Trp; Seq ID No: 53 Fmoc-D-Bheg-Glu-Asp-Chx-N-Melle-Trp; Seq ID No: 54 Fmoc -D-Bheg -Leu- Asp- He-N-MeChx-Trp; Seq ID No: 20 Fmoc-D-Bheg-Arg-Asp- He-N-MeChx-Trp; Seq ID No: 21 Fmoc -D-Bheg -Lys -Asp- He-N-MeChx-Trp; Seq ID No: 22 Fmoc-D-Bheg-'Orn-Asp- He-N-MeChx-Trp; Seq ID No: 38 Fmoc -D-Bheg -Asp- Asp- He-N-MeChx-Trp; Seq ID No: 24 Fmoc -D-Bheg-Glu-Asp- He-N-MeChx-Trp; Seq ID No: 25 Fmoc-D-Bheg-Leu-D-Asp-lie-Ile-Trp; Seq ID No: 2 ^ Fmoc -D- Bheg - Leu-D- Asp- Ile-N-Melle-Trp; Seq ID No: 20 Fmoc -D-Bhg- Leu-D- Asp- He- He -Trp; Seq ID No: 2 Fmoc-D-Bhg-Leu-D-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Ac-D-Txg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Ac -D-Txg- Orn- Asp- He -N-Melle-Trp; Seq ID No: 38 Ac -D-Txg-Lys -Asp- He -N-Melle-Trp; Seq ID No: 22 Ac -D-Txg- Asp-Asp-He-N-Melle -Trp; Seq ID No: 24 Ac-D-Txg-Glu-Asp-He-N-Melle-Trp; Seq ID No: 25 Ac -D-Txg- Phe -Asp- He-N-Melle-Trp; Seq ID No: 39 Ac -D-Txg -Arg -Asp- Ils-N-Melle-Trp; Seq ID No: 21 ? Ac-D-Txg-Asp- He-N-Melle-Trp; Seq ID No: 40 Fmoc -D-Txg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Fmoc -D-Txg -Orn-Asp- He-N-Melle-Trp; Seq ID No: 38 Fmoc -D-Txg -Lys -Asp- Ile-N-Melle-Trp; Seq ID No: 22 Fmoc -D-Txg -Asp- Asp- He-N-Melle -Trp; Seq ID No: 24 F oc -D-Txg -Glu- Asp- He-N-Melle-Trp; Seq ID No: 25 Fmoc -D -Txg- Phe- Asp- He-N-Melle-Trp; Seq ID No: 39 Fmoc -D-Txg -Arg -Asp- Ile-N-Melle -Trp; Seq ID No: 21 Fmoc -D-Txg -Asp- Tle-N-Melle -Trp; S-q ID No: 56 Ac -D-Tx - Leu-Phe-II e-N-Melle-Trp; Seq ID No: 41? C - D - Txg - Leu -? Sn - Ile - N - Melle - Trp; Seq ID No: 55? C-D-Txg - Leu-Glu 1 le-N-Melle-Trp; c "'1 ID No: 42? c -D- Txg - Leu-Gln - He-N-Melle-Trp; Soti ID No: 43 _ Ac-D-Txg-Leu-Tyr-Ile-N-Melle-Trp; Seq ID No: '44 Ac-D-Txg-Leu-l-Nal-He-N-Melle-Trp; seq ID- No: 45 Ac-D-Txg-Leu-2-Nal-He-N-MeIle-Trp; seq ID O: 45 Ac-D-Txg-Leu-Trp-He-N-Melle-Trp; SEQ ID O: 46 Ac-D-Txg-Leu-Asp-Val-N-Melle-Trp; seq ID NO: 47 Ac-D-Txg-Leu-Aep-Ile-N-MeVal-Trp; Seq ID No: 20 Ac-D-Txg-Leu-Asp-Chx-N-Melle-Trp; Seq ID O: 49 Ac-D-Txg-Leu-Asp-He-N-MeChx-Trp; Seq ID O: 20 Ac-D-Txg-Arg-Asp-He-N-MeChx-Trp; Seq ID O: 21 Ac-D-Txg-Lys - / \ sp-Ile-N-MeChx-Trp; Seq ID O: 22 c-D-Txg-Orn-? sp-He-N-MeChx-Trp; seq ID NO: 38 Ac-D-Txg-Asp-Asp-Ile-N-MeChx-Trp; Seq ID NO: 24 Ac-D-Txg-Glu-Asp-He-N-MeChx-Trp; seq ID O: 25 ? jgt Fmoc-D-Txg-Leu-Phe-He-N-Melle-Trp; SEQ ID NO: 4i W 'Fmoc-D-Txg-Leu-Asn-Ile-N-Melle-Trp; seq ID NO: 55 Fmoc-D-Txg-Leu-Glu-He -: T-Melle-Trp; Seq ID No: 42 Fmoc-D-Txg-Leu-Gln-He-N-Melle-Trp; eeq ID NO: 43 Fmoc-D-Txg-Leu-Tyr-He-N-Melle-Trp; Seq ID NO: 44 Fmoc-D-Txg-Leu-Asp-Val-N-Melle-Trp; seq ID O: 47 Fmoc-D-Txg-Leu-Asp-He-N-MeVal-Trp; Seq ID O: 20 Fmoc-D-Txg-Leu-Asp-Chx-N-Melle-Trp; Seq ID NO: 49 Fmoc-D-Txg-? Rg-? Sp-Chx-N-Melle-Trp; seq ID O: 50 Fmoc-D-Txg-Lys-Asp-Chx-N-Melle-Trp; Seq ID O: 51 Fmoc-D-Txg-Orn-? Sp-Chx-N-Melle-Trp; seq ID NO: 52 Fmoc-D-Txg-? sp-? sp-Chx-N-Melle-Trp; Seq ID NO: 53 Fmoc-D-Txg-Glu-Asp-Chx-N-MeIle-Trp; seq ID NO: 54 Fmoc-D-'Ixg-Leu-Asp-He-N-MeChx-Trp; Seq ID NO: 20 l'noc-D-Txg-Arg-Asp-Ile-N-MeChx-Trp; eq ID O: 21 Fmoc - D-Txg-Lys-Asp-He-N-MeChx-Trp; SEQ ID NO: 22 Fmoc-D-Txg-Orn-Asp-He-N-MeChx-Trp; Seq ID O: 38 Fmoc-D-Txg-Asp-Asp-He-N-MeChx-Trp; Seq ID NO: 24 Fmoc-D-Txg-Glu-? Sp-Ile-N-MeChx-Trp; Seq ID NO: 25 Et-D-Bhg-Leu-sp-Ho-Melle-Trp; Seq ID NO: 20 B.-D-Bhq-Leu-sp-Ile-N-Melle-Trp; s ID NO: 20 I'y -D-J ^ j-Leu-sp-Ile-N-Melle-Trp; r-q ID No-. twenty C.rl-D-Dhg-Leu-A? P-lle-N-Melle-Trp; : ID NO: 20 ? la-O-rbq-Lou -? '- ip-lle-N-Melle-Trp; v-q ID NO: 20 Cxi (U) -D-Bhg-Leu-Asp-He-N-Melle-Trp; seq ID No: 20 Me (U) -D-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 tBu-D-Bhg-Leu-Asp-He-N-Melle-Trp; seq ID NO: 20 CF3C0-D-Bhg-Leu-Asp-He-N-Melle-Trp; SEQ ID NO: 20 Et-D-Bheg-Leu-Asp-He-N-Melle-Trp; Seq ID NO: 20 Bc-D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID NO: 20 Pya-D -Bheg- Leu- Asp- He-N-Melle-Trp; Seq ID No: 20 Cxl-D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID NO: 20 Ada-D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID NO: 20 Cxi (U) - D- Bheg - Leu - Asp - He - N - elle - Trp; seq ID NO: 20 Me (U) -D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID No: 20 tBu-D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID NO: 20 CF3C0-D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID O: 20 Ac-D-Bheg-Leu-D-Asp-He-Ile-Trp; Seq ID NO: 20 Ac-D-Bheg-Leu-D-Asp-Ile-N-Melle-Trp; Scq ID O: 20 Ac-D-Bhg-Leu-D-Asp-He-Ile-Trp; Seq ID NO.- 2 Ac-D-Bhg-Leu-D-Asp-He-N-Melle-Trp; seq ID NO: 20 Ac-D-Bhg-Leu-Asp-Phe-N-Melle-Trp; seq ID NO: 56 Ac-D-Bhg-Orn-Asp-Phe-N-Melle-Trp; Seq ID NO: 57 Ac-D-Bhg-Lys-Asp-Phe-N-Melle-Trp; Seq ID NO: 58 Ac-D-Bhg-Asp-Asp-Phe-N-Melle-Trp; seq ID NO: 59 Ac-D-Bhg-Glu-Asp-Phe-N-Melle-Trp; Seq ID NO: 60 Ac-D-Bhg-Phe-Asp-Phe-N-Melle-Trp; Seq ID NO: 61 Ac-D-Bhg-Arg-Asp-Phe-N-Melle-Trp; SEQ ID NO: 62 Ac-D-Bheg-Leu-Asp-Phe-N-Melle-Trp; Seq ID NO: 63 c-D-Bheg-Om-Asp-Phe-N-Melle-Trp; seq ID NO: 57 Ac-D-Bheg-Lys-Asp-Phe-N-Melle-Trp; seq ID NO: 58 Ac-D-Bheg-Asp-Asp-Phe-N-Melle-Trp; Seq ID O: 59 Ac-D-Bheg-Glu-Asp-Phe-N-Melle-Trp; SEQ ID NO: 6c Ac-D-Bheg-Phe-Asp-Phe-N-Melle-Trp; seq ID NO: 61 Ac-D-Bheg-Arg-Asp-Phe-N-Melle-Trp; Seq ID No: 6 Ac-D-Bhg-Leu-N-MeAsp-He-He-Trp; and seq ID NO: 15 Ac-D-Dhg-Arg-? Sp-He-He-Tyr (CHO); scq ID NO-. 64 * or a pharmaceutically acceptable acid or base addition salt thereof.

The compounds of Formula I are valuable endothelin antagonists. The tests used indicated that the compounds of formula I possess activity endothelin antagonist. Thus, the compounds of Formula 1 were tested for their ability to inhibit binding in a receptor assay in accordance with the following procedures: [25lj-ET-l ([l25l] - Endothelin-1): ENDOTHELIN RECEIVER LINK TEST (ERBA-A) W INTELLECTUM CELL LINK OF I25I | -ET-1 Materials and Terms Used Cells The cells used were vascular soft muscle cells from the renal artery of rabbits cultured in a culture box. 48 wells (1 cm2) (confluent cells) 5 fi Culture Medium Culture medium was Dulbecco's Modified Eagles / Ham's F12 containing 10% fetal bovine serum and antibiotics (penicillin / streptomycin / fungizone). 0 Assay Buffer The assay buffer was a 199 medium containing Hanks' salts and 25 mM Hepes buffer (Gibco 380-2350A.I), supplemented with penicillin / streptomycin / fungizone (o.5%) and bovine serum albumin (I mg / mL). | l25l | -ET-l Amersham radioiodinated endothelin-1 [l 5l] -ET-l was used at a concentration of 20,000 cpm / or 25 mL (25 pM) Protocol First, add 0 5 mL of warm assay buffer (described above) to the aspirated culture medium and pre-incubate for 2 to 3 hours in a water bath at 7 ° C (do not put back on 5% carbon dioxide) ) Second, remove the assay buffers, place 1 50 μl of cold assay buffer described above to each well. one of [1251] -ET-1 cold and ligand competent to the solution (at the same time if possible) Then place the box in a water bath at 37 ° C for about 2 hours and carefully shake the box every 1 minutes Discard the radioactive incubation mixture in the basin and wash the wells 3 times with 1 ml of phosphate-buffered saline? Finally, add 250 ml of 0.25 molar sodium hydroxide, stir for 1 hour on a rotator and then transfer the sodium hydroxide extract to the gamma counting tubes and count the radioactivity.

LINK OF I 2 l | -ET-I IN CEREBRELLARY RAT MEMBRANES Materials and Terms Used Tissue Buffer The tissue is made of 20 m buffer (Trizma) of hydrochloride aminomethane tris (hydroxymethyl), 2 mm ethylenediaminetetra acetate, 100 μm of phenylmethylsulfonyl fluoride Preparation of the Primo Fabric, thaw an aliquot of frozen rat brain membranes (2 mg of protein in 0.5 ml). Next, add 0.5 ml of membrane aliquot to 4.5 ml of cold tissue buffer, polytron at 7,500 revolutions per minute for 10 seconds.

Finally, dilute the tissue suspension 1/100 (or 1 ml of suspension + 9.9 ml of tissue buffer), polish again and place ice.

Middle Dilution Buffer 199 with Hank salts plus 25 mm Hepes + 1 mg / ml bovine serum albumin. [, 25l] -ET-l [1251] -ET-1 from Amersham (aliquots of 2 x 106 cpm per 100 ml aliquot of [125I] -ET-l with 5.2 ml of solution buffer, place on ice until used (The final concentration ^^ will be 20,000 cpm per hose or 25 p.m.).

Protocol Add 50μl each of [1 51J-ET-1 cold and competent ligand to hoses on ice. Mix in 150μl of tissue to each hose, vortex briefly, then hit to force all liquids to the bottom (total assay volume = 250μl). Then place the hoses in a water bath at 37 ° C for 2 hours.

Add 2.5 ml of cold bath buffer (50 mm of Trizma buffer) to each hose, then filter and wash the hoses with 2.5 ml of additional wash buffer and add to the filter. Finally, wash the filtrates with 2.5 ml of additional cold wash buffer.

Count the radioactivity of the filtrates in a gamma counter ENDO TELINA RECIPIENTS TEST HUMAN (HERBA-B) LINK OF [125I1-ET-1 TO HUMAN CLONED RECEPTORS Isolation of the cDNA Human ETB receptor A cDNA library of human placenta was constructed in bacteriophage lambda gtl l and approximately 10 ° plates were selected with a restriction fragment 1.3 kilobase HindIII / Xbal labeled ~, 2p rat cDNA ETBR as a probe Hybridization of the plate was carried out for 16 hours at 42 ° C in a solution containing 100μg / ml of calf thymus DNA, I x Denhardt's solution, 5 x sodium saline citrate (SSC), jiBO mm sodium phosphate and 0. 1% sodium lauryl sulfate (SDS) The membranes were then washed twice for 30 minutes each in 2 x SSC and 0 1% SDS at 42 ° C.

A final wash was carried out at 0 5 x SSC with 0. 1% SDS at 55 ° C. The positive clones were purified and subcloned into a pUC19 plasmid. The DNA sequence was carried out by the dideoxynucleotide chain termination method and human ETBR (h ETBR) was identified by reading both DNA strands Transfection in CI Cells I-1 The restriction fragment I 35 kb Hindlll / Xbal of clone 12 of the HBET was inserted into the eukaryotic expression vector pRcCMV (pRcCMV-hETBR) The CHO-Kl cells were transfected with 20 μg of pRcCMV-hETBR by Electroporation at 300 V, 800 μF, low ohms for 1 second The cell population expressing human ETBR were chosen with G418 (0.5 mg / ml) and the clonal cell lines were isolated from these cell populations selected by single cell clone. The expiration levels of human ETBR were determined by the receptor binding assay described below using [125 I] -ET-3 as the radioligand. The CHO-K l cells were cultured in a mixture of Ham nutrient.

F12 and half of Dulbecco's Eagle (I I) DME / F12 (11) supplemented with 10% fetal bovine serum and G418 (0 5 mg / ml) Radioligand Link Assays Membranes were prepared from confluent transfected CHO-K l cells by lysis of cells in cold lysis buffers (5 mm N- [2-hydyoxyethyl] piperazine- N'- [2- acid atanesulfonic) (HEPES), 2 mm EDTA, pH 7 4), homogenizing with a Sfaomogenizer D "unce" A "and centrifuging the homogenate at 30,000 x g for 20 minutes at 4 ° C The cell pellets were suspended again in cold buffer (50mm Tris, 2 mm EDTA, 200 μm Pefabloc, l Oμm phosphoramidon, lOμm leupeptma, I μm pepstatin, pH 7. 4) and frozen at -80 ° C until use. The membranes were thawed and homogenized with a Brinkmann Polytron (Westbuiy, NY), then diluted in binding buffer (20 mm Tris, 2 mm EDTA, 1 0 μm Pefabloc, 100 μm bacitracin, pH 7 4) The radioligand and the competent ligands are pi eparate in binding buffer containing 0 1% bovine serum albumin (BSA) ll tei min? The binding assays were started by combining the membranes (0 7 μm. - human TUR, 3 μg of ETBR of l ata, | l 2'l | -1- I - I (30,000 cpm) and competent ligand in a final volume of 250 μl and incubating for 2 hours at 37 ° C. The filtration on Whatman GF / B filters was 50 mm Tris, pi l 7 4, containing 0.2% BS? and 1 0 μm bacitracin. Nonspecific binding was defined as binding in the presence of 100 nm of unlabeled ET-3 and the specific binding was defined as total binding minus the non-specific binding.The specific binding was analyzed by curve coupling in non-linear quadrants (InPlot , GraphPad Software, San Diego, California).

IN VITRO INHIBITION OF THE LIQUID ARTIST ACID BERATION OF ESTIM ULTIMATED BY ETL IN MUSCLES VASCULAR SOCKS OF CROP RABBIT (AAR-A) OR RAT CHO CELLS EXPRESSING ET RECEPTOR, RECOMBINANT (AAR- B) THROUGH COMPU THESE OF FORMULA I Antagonist activity is measured by the ability of aggregate compounds to reduce the release of aquidonic acid stimulated by endothelin in soft muscle cells t vasculai is in culture as release of ai chidonic acid (AAR ). The Loading Medium of Arachidonic Acid [H] (LM) is DME / FI 2 + 0 5% fetal calf serum (FCS) x 0 25 mCi / ml arachidonic acid [?) - (Ame? Sham) The confluent monolayers of vascular soft muscle cells from rabbit renal artery culture (AAR-A) or cells expressing the rat recombinant ET proteins (AAR-B) were incubated at 0 5ml of the LM more than 1 hoi as, 37 ° C, in 5% CO2 The LM was aspirated and the cells washed once with the test buffer (Hank's balanced salt solution [BSS] + 10 mm HEPES ^ BS? Libi e of fatty acids (1 mg / ml)) and sc incubated for 5 minutes with 1 ml of the preheated assay buffer. This solution was aspirated, followed by an additional 1 ml of preheated assay buffer and further incubating for 5 minutes. and lOμl of ET-l (0.3 nm) and the incubation was extended dui before 30 minutes. This solution then collected, 10 μl of scintillation cocktail was added and the amount of arachidonic acid ['H] was determined in a liquid scintillation counter ANTAGONISM IN VI ION OF THE VASOCONSTRICTION STIMULATED BY ET-l IN THE FEMORAL ARTERY OF THE RABBIT (E 1 \) AND THE \ o0? VASOCONSTRICTION ESTIM ULADA BY SARAFO IXINE 6c IN THE PULMONARY ARTERY OF THE RABBIT (ET ») New Zealand male rabbits were killed by cervical dislocation and exsanguination The femoral and pulmonary arteries were isolated, cleaned of connective tissue and cut into rings of 4mm. The endothelium was denuded by placing the rings on 5 hypodermic hoses (32 gauge for femoral rings and 28 gauge for tulone rings, Small Parts, Inc., Miami, Florida) and rolling them carefully. The denuded rings were mounted in 20 ml organ baths containing Krebs bicarbonate buffer (composition in nm: NaCl, 18.2, NaHCO3, 24.8, KCl, 4 (., MgSO4 7- H2O, 1.2, KH2PO4, 1.2; CaCl-2H2O, Ca-Na2 EDTA, 0.026, dextrose, 10.0) which was maintained at 37 ° C and 0 was continuously gassed with 5% C'0¿ in oxygen (pH 7.4) .The resting tension was adjusted to 3.0 g for the femoral arteries and 4.0 g for the pulmonary arteries, the rings were left for 90 minutes to balance The vascular rings were tested for the lack of functional endothelium (ie, lack of an endothelium-dependent relaxation response to carbachol (1 .0 μm) in contracted norepinephrine rings (0.03 μm) Peplide agonists, ET-1 (femoral) and S6c (pulmonai), were cumulatively aggravated in 10-minute increments.

The ET antagonists were agitated 30 minutes before adding the agonist and calculated TRANSPORT OF CACO-2 CELLS AND STABILITY IN THE INTESTINAL PERSUFACT OF ROOTS OF ENDOTHELIN ANTAGONISTS Transport experiments of CaCO-2 cells CaC-2 cells (human colon endocarcinoma cell line) were cultured in tissue culture flask T -75 from Coi ning and were passed from) to 80% confluent to • OX n new flasks (25 ml of poi fi c medium) using 1 ml of ipsin-EDTA and diluting with 10 ml of medium to stop the activity of trypsin for the samples, the cells were counted, then diluted to 2 ml. 5 x 10 5 cells / ml for plating (400 μl per well) on Snapwell culture membranes with 2 5 ml of medium in the lower chamber The medium in the Sanpwells was changed every 2 or 3 days The cells used for this sei experiments 5 were between passage 38 and 91 2- [N-Morpholino) ethanesulfonic acid (MES) + 33 5 mm glucose or tle buffer was incubated for all and all incubation solutions were prepared at an asymmetric pressure of 280 to 300 millimoles. The concentration of the endothelin antagonist under study (for all experiments) was 100 μm and another endothelial antagonist with similar HPLC characteristics (time of 0 retention 2-3 minutes from the antagonist under study and similar chemical characteristics) Using a 25μm concentration as an internal standard to compensate for any deficiency. Before the start of the experiment, the transepithelial electric resistance (TEEK) sc midi pai at each Snapwell has medium) cn ti is points on the membrane Any membrane with gl Andes variations in the li is \ alo? is not used since the above suggests compromises in the cell monolayer the membranes were washed ^ by stirring them in 0.9% normal saline and 1 mg / ml of human serum albumin were mounted in the diffusion chambers for 2 hours at 37 ° C with O2 in air-dried bubbles at 37 ° C overnight, then with 4 5 to 5 0 ml of dosing solution 5 (MES + glucose + 14C-PEG-4000 (5000 dpm / 50 μl + drug) for 5 minutes and 4.5 to 5.0 ml MES -t glucose rinse just before the experiment] apical side (donor) was filled with 4 5 to 5 ml of dosing solution, the basolateral side (recipient) with MES + glucose. The samples were removed from the donor compartments and the course of the experiment and analyzed by 14C-PEG- 4000 (integrity and endothelin content) The amount of drug transferred as a function of time was used to calculate the apparent permeability, Pa? L | = (V / (A * C ")) (dC / dt) where V is the volume of the receiving chamber (4.5 or 5.0 ml), A is the exposed surface of the cell monolayer (1. 1 cm2), C "is the co Donor drug concentration and dC / dt is the 5 change in the drug concentration of the recipient with the passage of time. Concentration ^ = initial of each diffusion chamber was used for its individual C value. The values in Table I suggest that Examples I, 16 and 19 may have 5-10% absorption in the intestine. 0 Stability in the Rat Intestinal Perfusate For stability experiments, male Wistar rats of 250-300 g were fasted overnight, then anesthetized with a Ketamine / Xylasin mixture (prepared just before li injection) in the muscle of the epidermis followed by a pentobarbital injection in the alternative crotch muscle After a deep anesthesia, verified by the loss of the reflex injection, an incision was made in the midline intestine by perfusion The segment was perfused for 90 minutes with MES buffer to a flow rate of 30 ml / minute using a Harvard Apai ato perfusion pump in the infusion / fill mode The pei use was maintained at 37 ° C for each experiment. A water bath at 37 ° C in oscillation established in 90 cycles (minutes was used in all the examples.

The experimental time course for the compounds studied was 0, 1, 3, 5, 7, 10, 15, , 30, 60, 90, 120 and 10 minutes (with some variations for individual compounds). i.y The reactions were run as follows. 90μl of perlusate plus 1μl of endothelin antagonist (250μl normal in MES buffer for most compounds) followed by a short vortex and incubation dui for the indicated time. Zero time was prepared by adding 100 μl ACN and 90 μl per use, applying vortex, then adding 10 μl of normal drug, applying vortex All samples were centrifuged for 10 minutes at 5 14,000 rpm in an Eppendorf centrifuge for pellet centrifuged proteins . For the HPLC, 50 μl of the supernatant inal was injected and the loss of the original and appearance of the metabolites was examined. The half-life determinations were calculated based on the maximum loss of the original using the calculation:? l 2 = LN (2) / k 0 where k = slope of the initial linear l ango of the experiment The enzymatic activity of peptidaso amino leucino in pei fusato was determined as a conventional marker. The values in Table I show the improved stability of Example 19 Lick scintillation counting Fifty microliter samples were collected from all time points and from each of the chambers, placed in 20 ml silage bottles. , 10 ml of Ready-Gel was added. All samples were allowed to stabilize for at least 1 hour before counting. Samples were counted in the Packard T iCarb 4000 for 5 minutes each in dpm mode for 3 cycles. To assure that there were nomilumines present, the second and third counts were normally used in the calculations. When the membranes were analyzed by radiolabel reception, they were solubilized with 0 5 ml of Soluene-3 0 for at least 30 minutes and then neutralized with 0 I ml of a saturated solution of sodium pyruvate in methanol, glacial acetic acid and methanol in the proportion of 4 3 1 by volume (PGM) after addition of scintillant te (10 ml) and counting as indicated above Analysis of H PLC (High Pressure Liquid Chromatography) For the explanatory samples of C'aCO-2, 20 to 50 μl of the donor compartments were removed, 150 to 200 μl of the receptor compartments at each time point. internal (solubilized in 95-99% ACN / H2O) was measured in Eppendorf hoses of I 5 ml in a volume equal to the volume of the receiver collected (MES + glucose added to the hoses of the donor compartment to equal the final recipient volume ) within 30 minutes of trying the time point. Aliquots of time points were added to the Eppendorf hoses, mixed, then 125 μl was injected into the HPLC denti. When the membranes were analyzed by endothelial reception, the cells were added to the cell by adding 250 μl or 1 Triton with brief vortex, sonicating 15 minutes and rinsing the hose with an equal volume of internal HPLC gradient method. all samples were used ^ experiments on CaCO-2 cells and stability experiments) Mobile phase A = 90% H2O, % ACN, 0 1% TFA, pl l 3 5, mobile phase B = 24% H2O, 76% ACN, 0 1% TFA, pH 3.5; 100% A for 100% B for 20 minutes, 100% B for 100% A for 20 to 22.5 minutes and 100% A for 22 5 to 27 minutes The pH of both movable phases was adjusted after the addition of all components with NaOH Analysis of Pcptidaso Aniiuo Leu ciña 0 llf ^ A 0 9 ml of MES buffer (blank) and 0.9 ml of pei sufato were added a solution of 0 1 ml of L-leucine-p-nitroanilide hydrochloride (LpNA) The solutions were mixed quickly and a 5-minute kinetics program was run on the Beckman DU-70 spectrometer (380 nm wavelength, 10-second time intervals) to monitor the formation of p-nitroaniline jj DURATION OF CONSCIOUS RA TES OF THE STATE OF ACTION Use was made without fasting for 350-500 g and anesthetized with Metho- nane (methoxyflurane) by inhalation. The rats were cannulated in the jugular (PE50) for IV administration of maeamilamma- (' II (MEC), ET- ly and Ac-D-Bhg-Lcu-Asp-Ile-N-Melle-Trp (Example 19) and canulaion in the cairolate (PESO) for arterial blood pressure measurements The rats were attached to a swivel to have freedom of movement and food and water were made available. • Before the experiment the animals were allowed to recover from anesthesia for 60 minutes. The cells were blocked ganglionically with MLC I 25 mg / kg. kμ IV 20 minutes before pi ueb.i of ET-l Ac-D-Bhg-Leu-Asp-Ile-N-Melle-Trp (Example 19) was administered in a dose of 10 mg / kg IV.

Juste compound inhibited the ET-1 driving activity by 1% and 58% in 5 and 30 minutes after the dose, respectively (n = 4 at each time point) The above illustrates the prolonged activity of Ac-D-Bhg -Leu-Asp-lle-N-Melle-Trp (Example 19) in vivo. 5 STUDY OF L? INDUCED ACUTE RENAL FAULT OR ISCHEMIA Male rats (300-4O0g) of Sprague-Dawley were housed in metabolic cages for 2 days before and 7 days after renal injury; levels of urine output and plasma creatinine were monitored daily On the day of kidney injury, rats were anesthetized H) "with sodium pentobarbital (50 mg / kg, IP) heparinized (50 units, IP) and were instrumented with a cannula in the vein of the tail for infusion of drugs or vehicle, both kidneys were exposed by means of an incision in the flank and the right kidney was removed.

The left renal artery was pressed for 60 minutes and released. Example 1 was infused for 60 minutes before and after the ischemic period. The renal lesion was evident 1 and 2 5 days after the ischemia from tic an increase ten fold creatine levels The plasma and significant decrease in urine output Mortality occurred mainly between the second and the third day after the injury. However, the mortality was significantly lower (52%, N = 23) in rats treated with the Example 1 compared to vehicle rats (83%, N = 23). In addition, the urine output on the second 0 day after the kidney injury was significantly greater in the animals treated with the Example 1 . Creatine levels were not different from manet a significant between the treatment groups in the first and second days after the injury (Haleen S., et al., FASEB .1., April 1994) Therefore, these data show that Example 1 and the analogues listed in Table I are effective in a model of renal failure induced by ischemia.

The data in Table I below show endothelin receptor binding, antagonist activity, CaCO-2 cell resistance, metabolic stability, and effectiveness in a model of acute renal failure induced by the ischemia of compounds representative of the compounds. of Formula I $ m L-Bhg-Leu-Aep * 2.5 3.0 2.36 Seq ID No: 2 Ile-Ile-Trp Ac- -Bhg-Leu- 0.56 0.71 0.56 Seq ID No- '2 Asp-Ile-Ile-Trp Ac-D-Txg-Leu 0.018 0.18 0.05 0.062 Seq ID No. 2 Asp-Ile-Ile-Trp Ac-D-Bheg-Leu-0.0C5 0.019 0.003 0.017 6.8 7.4 Be ID No- 2 Aep-Ile-Ile-Trp Ac-D-Bhg-Orn- 0.022 1.5 0.037 6.5 Seq ID No: 3 Asp-Ile-Ile-Trp Ac-D-Bhg-Glu- 0.0055 0.022 0.007 0.027 6.5 7.0 Be ID No- '6 Asp-Ile-Ile-Trp Ac-L-Oxn-Lys- 0.05 0.93 Seq ID No- 4 Asp-Ile-Ile-Trp Ac-D-Oxn-Lys- 0.12 0.55 s ID N ?; Asp-Ile-Ile-Trp t L-Txg-Leu-Asp- 4.5 2.1 s ID H Ile-Ile-Trp _ ^ Ac-L-Txg-Leu- 1.5 2.1 Seq ID No: 2 Asp-Ile-Ile-Trp D-Txr-Leu-Asp- 0.33 0.38 0.32 2.4 Seq ID No: 2? Le-IIe-Trp Ac-D-? Hg-Arg- 0.0012 0.04 Seq ID No: 8 P _, - 1 le -lie -Trp Ac-D-3hg-Leu-N- 0.44 1.9 Seq ID No: 15 KeAsp-Ile-Ile-Trp 'Ac-D-Bhg-Leu-D- 0.14 0.4 37.4 ± 6.4 0.95 ± 0.19 Seq ID No: 2 Asp-Ile-Ile-Trp.-C-D-Bhg-Leu 0.068 0.03 Seq ID No: 31 A = -Phe -lie -Trp Ar-D-Bhg-Arg- 0.079 4.9. Seq ID No: "64 A - Ile -Ile -Trp General Method tiara preñara Compounds of Formula I Compounds of Formula 1 can be prepared by peptide synthesis solid phase in a peptide synthesizer, for example, a synthesized! "of Applied Biosystems 430A peptides using amino acids protected with activated esters or N-alpha-Boc anhydrides, on PAM or MBHA resins, In addition, the compounds of the Formula I can also be prepared by the synthesis of peptides in conventional solutions The amino acid side chains are protected as follows: Bzl (Asp, Glu, Ser), 2-C1-Z (Lis), 2-Br-Xfl ir) , Bom (His), For (Trp) and MeB / l (Cis) Each resin g) is split with 9 ml of HF and 1 ml of anisol or p-ci esol as a cleaner at 0 ° C) The peptide is washed with cyclohexane, extracted with 30% aqueous HOAc, followed by glacial HOAc, concentrated under reduced pressure and lyophilized. (A peptide containing For (Trp) is dissolved at 0 ° C, the pH is adjusted to 12 5 with INK KOH (2 minutes), it is neutralized with glacial HOAc, it is scrubbed in C (as described below) and the freeze-dried peptide is puulized by high performance reversed phase high performance liquid chromatography (RP-HI'LC) on a C ?? column (2 2 x 25.0 cm, 15.0 with a linear 1 gi 1 gi). % TFA in water at 0 1% TFA in acetonitrile and lyophilisate The homogeneity and composition of the resulting peptide is verified by RPHPLC, capillary electrophoresis, thin layer chromatography (TLC), proton nuclear magnetic resonance (NMR) spectrometry and Mass spectrometry of fast atom bombardment (FAB-MS) The compounds of the present invention can be administered and administered in a wide variety of oral and parenteral doses. Thus, the compounds of the present invention can be administered! measured me injection, that is, in ?? a \ enosa, intramuscular,. intracutaneous, subcutaneous, inlraduodenal or intraperitonally. Also, the compounds of The present invention can be administered by inhalation, for example, "In addition, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following 5-dose forms can comprise as the active component, either a compound of the Formula I or an acceptable pharmaceutically acceptable salt of a compound of Formula I.

To prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. The The solid form preparations include powders, tablets, pills, capsules, pills, suppositories and dispersible granules. A solid carrier can be one or more substances which can also act as diluents. flavoring agents, bonds, preservatives, tablet disintegrating agents or an encapsulating material.

In powders, the carrier is a finely divided solid that is in a mixture jjficon the finely divided active component In tablets, the active component is mixed with the carrier having sufficient binding properties in appropriate proportions and compacted in the desired shape and size.

Powders and tablets p? They preferably contain from five or ten to about one-third percent of the active compound. Suitable poi tadoi are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, carboxymethylcellulose, a low melting wax, and the like. The term "preparation" is intended to include the formula of the encapsulating material as a carrier that provides a capsule in which the active component with or without other carriers is surrounded by a carrier, which in turn is related to it. Similarly, pills and tablets are included. Tablets, powders, pills, lozenges and tablets can be used as solid dose rations appropriate for oral administration To prepare suppositories, a low-melting wax, such as a glyceride of fatty acid or cocoa butter, melts and the active component is dispersed homogeneously therein, stirring. The melted homogeneous mixture is then poured into molds of suitable size, they are allowed to cool and therefore solidify.

Liquid form preparations include solutions, suspensions and emulsions, eg, water solutions or propylene glycol in water. For parenteral injections, liquid preparations can be formulated in solution with aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be removed by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and oiling agents as desired • Aqueous suspensions which are ready for oral use can be made by dispersing the component active finely divided in water with viscous material, such as synthetics, resins, methylcellulose, carboxymethylcellulose and other well-known suspending agents Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These piperaments may contain, in addition to the active component, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickening agents and solubilizers and the like.

The pharmaceutical preparation is preferably in the form of doses per unit. In this form the preparation is subdivided into doses per unit containing appropriate quantities of the active component. The dosage form per unit can be a j-shaped preparation, the package contains discrete quantities of the preparation, such as tablets, capsules and powders. packed, in vials or ampoules Also, the dosage form per unit can be a capsule, tablet, pills itself or it can be the appropriate number of any of these in packaged form The amount of active component in a dose preparation per unit can be varied or adjusted from 0 I mg to 100 mg preferably from 0 5 mg to 100 mg according to the particulai application and the potency of the active component. The composition can, if sc It also desires to also contain a therapeutic agent or therapeutic compatible use as an endothelin anlagonist, the compounds used in the pharmaceutical of this invention are administered in the initial dose of about 0.1 mg up to about 20 mg poi kilogram daily. A daily dose range of about 0.01 mg to about 10 mg per kilogram is requested. Doses, however, may vary depending on the patient's requirements, the severity of the condition being treated and the compound used. The determination of the appropriate dose for a particular situation is within the practice of the technique. In general, treatment starts with doses smaller than the optimum dose of the compound. From "then, the dose is increased by small increments until the optimal choice under the circumstances is reached. For convenience, the total target dose can be divided and administered in portions during the day, if desired The following non-limiting examples illustrate the methods preferred by the inventors for pi epat ar lus compounds of the invention.

S E EMPLOY 1 Ac-D-Bhg-Leu-Asp-Ile-lle-T? Sequence Identification Number: 1 The linear hexapeptide was prepared by the solid phase synthetic peptide methodology using a Boc / benzil strategy (Stewart JM and Yuung .1 D., Solid Phase Peptide Synthesis, Pierce Chemical Co, Rockford , Illinois, 1984) All of the protected amino acids and lus i cactive are obtained from commercial sources with the exception of N-a-Boc-DL-Bhg and are not further purified. The peptide resin peptide is prepared in a synthesizer. of peptidus? pplied B? us \ siems 430A, using pi utuculus provided by a coupling scheme mediated by dicyclohexylcarbodiimide (standard 1.0, fsion 1 .40) Starting with OJ IO < • of Na-Boc-Trp-PAM resin (0 70 meg / g, 0.497 meq Boc-1 rp (For) total) the piutegido peptide is prepared by coupling the following amino acids in steps (in addition steps) ): Na-Boc-Ile-ü 5H2O, Na-Boc-Ile-0.5H2O, Na-Boc-Asp (Bzl), Nu-Boc-Leu-H2O and Na-Boc-DL-Bhg A typical cycle for coupling of an individual amino acid residue is illustrated below (reproduced from manual ABl) All single coupling cycles conform to the following pattern- 1) 33% TFA in DCM for 80 minutes 2) 50 of TFA in DCM din ¡inte 18 5 minutes 3) Three washes in DCM 4) 10% of DI LA in DMF for 1 minute 5) 10% of DILA in DMF for I minute 6) Five washes in DMF 7) Coupling iodine 8) Five washes in DCM After the coupling of N-a-Boc-DL-Bhg, the Boc sc group removes with the final NH2 cycle O 012 g) The peptide is released from the solid support and the carboxylate of the aspartic acid deprotected by the attachment with anhydrous hydrogen fluoride (9 ml), anisol (0.5 ml) and dimellil sulphide (0 5 ml) ((- -> minutes, 0 ° C.) After removing the hydrogen fluoride under a nitric oxide blanket, the resin is washed with ethyl ether (3 x 30 ml) and extracted with 20% HOAc in water (3 [mu] M) ml. Glacial HOAc (2 x 30 ml) The extractions are concentrated under reduced pressure and lyophilized (360 mg). Peptide 0 ml of 50% 'I l-? / H2O, is filtered through a lilti or 0.4 1 syringe, and chromatographed on a Vydac 218TP 1022 column (2.2 x 25 0 cm, 15.0 ml / min, A: 0.1% TFA / H2O, B 0 1% TFA / CFLCN, Gradient, 0% B for 10 minutes, 10% to 40% B for 120 minutes) Two individual fractions are collected and combined based on analytical HPLC analysis The combined fractions are concentrated separately under reduced pressure (1 mL), diluted with Fl2O (50 mL) and lyolized (40 mg / each).

Subsequent (isomer B) is repurified under the same experimental conditions with a gradient of 30% to 50% for 120 minutes at 15 ml / min to produce the purified product. The acetylation is carried out with 20 mg of Isomer B in 90% acetic acid followed by the addition of acetic anhydride (5 ml) and stirring overnight din. After evaporation and drying the product Ac-D-Bhg-Leu-Asp-lle-Ile-Trp Number of sequence 2 is 99% pure by HPLC | Column Vydac 218 TP 1022 (2 2 x 25 0 cm, I 5 ml / min A: 0.1% TFA / CH, CN, Gradient 20% to 80% B for 22 min)] t, < = 18 66 minutes. The homogeneity and structure of the resulting peptide is confirmed by analytical HPLC. Piolon Nuclear Magnetic Resonance Spectroscopy (H-NMR) and Rapid Atom Bomba de Oro Mass Spectroscopy (FAB-MS), M + Na 972.0, M + 2Na + 995 9 In an analogous pi encourage appropriate cides, the corresponding ones of Fot muía I are prepared as follows EXAMPLE 2 D-Bhg-Leu-? Sp-lle-lle-Ti p. I? B-MS, M + l 907 4 Sequence Identification Number. 2 EXAMPLE 3 L-B -Leu-Asp-lle-lle-Trp. F? B-MS, M + l 907.4 10 9 ^^ Sequence Identification Number: 2 AND EMPLOY 4 AC- L-Blm-Lcu-Asp-lle-lle- 1? p, FAB-MS, M + l 950 0 Sequence identification number: 2 5 EXAMPLE S Ac-D-Txu-Blm-Leu-Asp-Ile-lle-Trp, FAB-MS, M + Na 977 0 Number of Sequence identification: 2 0 EXAMPLE 6 Ac-D-Bheμ-Lcu-Asp-Ile-llc-1 1 p FAB-MS, M + Na 970 3 Sequence Identification Number. 2 EJ EMPLO 7 Ac-D-Blm-O? n- Asp-lle-Ile-T? p FAB-MS, M + l 95 1 2 Sequence Identification Number: 3 EXAMPLE 8 Ac-D-Bhü-Glu-Asp-lle-Ile-Ti p. FAB-MS, M + Na 988 8. Sequence Identification Number: 6 EXAMPLE 9 Ac-L-Oxn-Leu-Asp-lle-lle-Ti p. FAB-M + Í 936.6 10 9 ~ ^ Sequence Identification Number: 4 EXAMPLE 10 Ac-D-Oxn-Leu-Asp-Ile-Ile-Ti p, FAB-MS, M + l 936 6 Sequence Identification Number: 4 5 AXIS LO 11 L-Txg-Leu-Asp-lIc- lle-Trp. FAB-MS, M + l 913 1 Sequence Identification Number: 2 0 EXAMPLE 12 Ac-L-Txu-Leu-Asp-lle-Ile-Ti, I AB-MS, M + Na 977 2 Sequence Identification Number: 2 I I EM LO 13 í D-Txu-Leu-Asp-lle-Ile-Trp. f? B-MS, M + l 912.2 Sequence Identification Number: 2 EXAMPLE 14 Ac-D-Bhg-Ai g- Asp-lle-Ile-Ti p. FAB-MS, M + l 994 6 Sequence Identification Number: 8 EXAMPLE 15 Ac-D-Bhg-Leu-N-MeAsp-l le- 1 le-Trp, FAB-MS, M + l 964 0 * W Sequence Identification Number: 15 EXAMPLE 16 Ac-D-Bhg-Leu-D-Leu-Asp-lie-1 le-Trp. FAB-MS, M + l 950 4 Sequence Identification Number: 2 EXAMPLE 17 Ac-D-Bhg-Leu-Asp-Fe-lle-'l i p. FAB-MS, M + Na 1006 5 Sequence Identification Number: 31 EX EMPLOYMENT 18 Ac-D-Bhg-Arg-Asp-Ile-lle-Ti (For). FAB-MS, M + l 102 1 6 Sequence Identification Number: 64 E EMPLO 19 t Ac-D-Bhg-Leu-Asp-lle-N-Mellc-T? P. FAB-MS, M + l 963 6 ~ Nume? or Sequence Identification 20 # EXAMPLE 20 Saldisodium from Ac-D-Bhg-Leu-Asp-lle-Ile-Trp Numei or Sequence Identification 2 A satinated solution of sodium bicarbonate in water was added, diluted with water (10%), cooled to 0 C and 10 ml of the solution were added to approximately 50 mg of Ac-D-Bhg-Leu Asp-lle-Ile-Trp Sequence Identification Number 2 (Example 1) stirring The pH of the solution is greater than 9 After 10 minutes, the solution is passed to you birds of a C 18 cartridge, washed with water (100 ml) and the absorbed peptide is eluted with melanol (50 ml), concentrated under reduced pressure, resuspended in water (50 ml) and lyophilized (three times) to give the title compound t-D- Bhg-Leu-Asp-Ile-llel, disodium salt, FAB-MS, M + l 950 4 M i Na 972 1, M + 2Na 994 3 Number of Sequence Identification 2 EXAMPLE 21 Boc Bhg Bhg HCl (l 70 g 5 43 mmol) is suspended in 150 ml of H 2 O (2 1) at room temperature? the solution i. Then, 40 g (6 42 mmol) of di-tert-butylcarbonate are added. The pFl of the solution si. a¡usta a > 9 0 with I N NaOl l and sc maintains between pH 9 and 10 with aliquots of I \ \? OH, until the pH is consumed The solution is concentrated under reduced pressure to ap? 75 ml, covered with ethyl acetate (50 ml) • and acidified to approximately 2 ^ pH with 10% aqueous 11C1 The organic layer was 10% aqueous (2 x 50 ml), pitch (2 x 50 ml), H2O (3 x 50 ml) and dried with MgSO The solution was concentrated, concentrated under reduced pressure and the oil was recrystallized from ethyl acetate heptane (1.82 g). The white solid was decayed by NIMR proton, mass spectrometry of rapid atom bombardment (M + 1 = 368 ) and elemental analysis.

LIS I OF SEQUENCES (1) GENERAL INFORMATION (i) Applicant C d, Wayne L. Doherty, Annette M 'I upliss, John G. (ii) Title of the Inno ciation ANTAGONISTS II OF ENDOTHELIN (iii) Number of sequences 64 (iv) Address for Coi respondence. (A) Destination One Warner-Lambert Company (B) 2X00 Street Piymouth Rd (C) Ann Arbor City (D) State Michigan (L) United States of America (F) United States Postal Area 48 105 (v) Foi ma for reading. i in computer (A) Type of media "Flexible disk (B) CompuUdoia Compatible with IBM (C) Operational system PC-DOS / MS-DOS (D) Piogiama Je computed Patentln veision # 10, see # 125 (vi) Dalos de the current Application (A) Number of the application (B) Date of entry (C) Classification # ^ (vp) Data of previous applications (A) number of the application US 08 / 033,515 (B) date of entry 31 of Maizo de 1 93 (vu) Inhumation of the Bogado / Agent (A) Name I, Fiancis J (B) Legislature number 33069 Jg () Legistio number / certificate PD-4V.4-P2 (lx) Telecommunication inflow (A) ) Telephone i 13996-7295 (B) Fax .p 996-1553 (2) Information for sequence identification numbers (i) C ARACTERIS I AS OF SEQUENCE 1 (?) LONGI I I 1) 6 animo acids (B) UPO amino acid (C) FJLAM1- NTATION. only - (D) TOPOI OGÍA- linear (ii) TI PO DE MOLECULA. peptide (xi) SEQUENCE DESCRIPTION- No Sequence ID: 1: Xaa Xaa Xaa Xaa Xaa Xaa (2) Information for the identification of sequence number 2 (i) CHARACTERS 'I ICAS OF THE SEQUENCE V (A) LONC p UD 6 amino acids (B) TYPE amino acid (C) FILAMLNTACIÓN unique ([)) TOPOLOGÍA. linear (ii) TYPE OF MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID: 2: (2) Information for the identification of sequence number 3 (i) CHARACTERS! ICAS OF THE SEQUENCE (A) LONGI 1 1 D 6 amino acids (B) TYPE amino acids (C) FILA MI N I'ATION unique (D) rOPOI OGY linear (ii) TYPE OF MOLECULE. peptide UENCIA: No Sequence ID: 3: 1 5 (2) Information for identification of sequence number 4- (i) CHARACTERISTICS OF THE SEQUENCE. (A) LENGTH: 6 amino acids (B) TYPE amino acid ^ (C) F1L? M I .NT ATION- unique (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE- peptide (xi) DESCRIPTION OF SEQUENCE. No Sequence ID: 4: Xaa Lis Asp He lie Trp 1 5 # (2) Information for the identification of sequence number 5 (i) CHARACTERS I ICAS OF THE SEQUENCE (A) LONGI TUD: 6 amino acids (B) TYPE amino acid (C) F1LAM IN PACIFIC only (D) TOPOLOGY: linear ( ii) TYPE OF PECIFIC MOLECULE (xi) SEQUENCE DESCRIPTION: No de. Sequence ID: 4: Xaa Asp? Sp He rp (2) Information for the identification of sequence number 6- (i) CHARACTERISTICS OF THE SEQUENCE: (A) LONG II UD: 6 amino acids (B) TYPE amino acid (C) FILAM ENTAC1ÓN: unique (Dj TOPOEOCiÍA: 'linear? (ii) TI PO OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: No of Sequence ID: 6: Xaa Glu Asp He lie Trp (2) Information for the identification of sequence number: 7. g (i) CHARACTERS I ICAS OF THE SEQUENCE. (A) LONGI TUD: 6 amino acids (B) TYPE amino acid (C) FILAM E TATION: unique (D) TOPOLOGY: linear (ii) TI PO DE MOI I .CULA. peptide (xi) SEQUENCE DESCRIPTION Sequence ID No.: 7: Xaa Fe Asp lie lie Trp (2) Information for the identification of sequence number 8 (i) CHARACTERI S I ICAS OF THE SEQUENCE (A) LONGI I UD. 6 amino acids (B) TYPE amino acid (C) FILAMENTACIÓN unique (D) TOPOLOGÍA. linear (ii) TYPE OF MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID. 8: Xaa Arg Asp lie lie Trp (2) Information for the identification of sequence number 9 (i) CHARACTERS 1 ICAS OF THE SEQUENCE (A) LONGIT UD: 5 amino acids (B) TYPE amino acid (C) FILAM IN TACIÓN. unique (D) TOPOI OGÍA- linear (ii) TI PO DE MOI CULA peptide (xi) SEQUENCE DESCRIPTION. No Sequence ID: 9: Xaa Asp He He Ti (2) Information for sequence identification number 1 (i) CHARACTERISTICS OF THE SEQUENCE (A) LONGIIUD '6 amino acids (B) TYPE amino acid (C) FILAMENTACIÓN unique (D) TOPOLOGÍA lineal (ii) TYPE DEMOLÍ CULA peptide (xi) SEQUENCE DESCRIPTION No Sequence ID- 10- Xaa Leu Fe He He Trp (2) Information for the identification of sequence number I 1 (i) CHARACTERS I ICAS OF THE SEQUENCE (A) LONGI I UD 6 amino acids (B) TYPE amino acid (C) FILAMENTACIÓN unique (D) TOPOI OGIA linear ft (ii) ) TYPE OF MOI I CULA peptide (xi) SEQUENCE DESCRIPTION No Sequence ID: ll- Xaa Leu Asn He He Tip 1 ^ (2) Information for sequencing use number 12 (i) CHARACTERS I l (SEQUENCE AS (A) LO iIll D 6 animo acids (B) TYPE amino acid - (C) FILAM IN ATION unique (D) TOPOLOGY, linear (ii) TI PO OF MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE: No of Sequence ID: 12: Xaa Leu Glu He lie Trp 1 5 (2) Information for the identification of sequence number 13 lüf ^ (i) CHARACTERS TICAS OF THE SEQUENCE (A) LENGTH: 6 amino acids (B) TYPE amino acid (C) FILAMLNTAC1ÓN- unique (D) TOPOI OGIA linear 5 (ii) ) TYPE OF MOLECULE peptide UENCIA No Sequence ID: 13: 0 (2) Information for the identification of sequence number 14 (i) CHARACTERISTICS OF THE SEQUENCE (A) LONCi rUD 6 amino acids (B) TYPE amino acid (C) PHILAN I I NT N TION (D) TOPO! Linear OG1A (ii) TYPE OF MOI i CULA peptido (xi) SEQUENCE DESCRIPTION No Sequence ID 14 (2) Information for identification of sequence number 15 (i) CHARACTERS I ICAS OF THE SEQUENCE ' (A) LONGI 1 UD 6 animo acids ü -íl-k 0 / r (B) TYPE amino acid (C) F1LAM LNTACION unique (D) rOPOl OGIA linear (u) T IPO DE MOLECULA peptido (xi) SEQUENCE DESCRIPTION No Sequence ID 15 Xaa Leu Xa «? He He Ti p (2) Information for sequence identification number 16 (i) CHARACTERISTICS OF THE SEQUENCE 0 (A) LONGI I UD 6 animo acids (B) TYPE of acid mood (C) FILAMEN I ACION unique (D) I OPOI OC1A linear (n) U PO OF MOI I CULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID: 16: * (2) Information for the identification of sequence number 17 (i) CHARACTERS I ICAS OF THE SEQUENCE (A) LONGI I UD 6 amino acids (B) TYPE amino acid, (C) FÍLAME. Unique N TATION V (D) Linear TOPOLOGY (ii) TYPE OF MOLECULE peptide (xi) SEQUENCE DESCRIPTION No Sequence ID: 17: Xaa Leu Asp Val He Ti p J (2) Information for the identification of sequence number 1 (i) CHARACTERI S ICAS OF THE SEQUENCE (A) LONGI I UD 6 animo acids (B) TYPE amino acid (C) T ILAM IN TACION unique (D) TOPOLOGÍA lineal (ii) TYPE OF MOI I CULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID. 18: Xaa Leu Asp He \ al Ti p (2) Information for the identification of sequence number 1 (i) CHARACTERS "! ICAS OF THE SEQUENCE - (A) LONGI ID 6 amino acids (B) TYPE amino acid (C) F1LAMI NTAC1ON unique (D) TOPOI OGIA linear (ii) TYPE OF MOLECULE 'peptide r (xi) DESCRIPTION OF SEQUENCE No of Sequence ID 19: 1 5 (2) Information for the identification of sequence number 20 (i) CHARACTERI SI ICAS OF THE SEQUENCE (A) LONGI IE 6 animo acid (B) TYPE animo acid (C) F1LAM I NT ATION unique (D) TOPOI OGIA linear (ii) ) TI PO OF MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID. 20: Xaa Leu Asp He Xaa Trp (2) Information for sequence identification number 2 I (i) CHARACTERS! ICAS OF THE SEQUENCE (A) LONGI I D 6 amino acids (B) TYPE amino acid (C) FILAM1-NTATION: unique (D) TOPOI Oí A linear (ii) TYPE OF MOI LCULA peptide (xi) DESCRIPTION OF SEQUENCE. No Sequence ID: 21: Xaa Arg Asp He Xa.i Trp 1 100 ^^ (2) Information for the identification of sequence number 22 (i) CHARACTERS TICAS OF THE SEQUENCE (A) LONG I I l D. 6 amino acids 15 (B) TYPE amino acid (C) F1L? MENTATION- unique (D) TOPOI OGY. linear (ii) TYPE OF MOI HCULA peptide (xi) SEQUENCE DESCRIPTION No Sequence ID: 22: 0 Xaa Lis Asp He Xaa Trp i (2) Information for sequence identification number 23 (i) C AR? CTERI S I ICAS DE L? SEQUENCE (?) LONGIIUD 6 animo acids (B) TYPE amino acid (C) FIL? Single MENGATION (D) IOPOI OG1A linear (n) TYPE OF MOLECULE peptide (xi) DL SCRIPTION OF SEQUENCE No of Sequence ID 23 Xaa Xaa Asp He \ aa Trp 1 5 itr (2) Information for the sequence identification number 24 (i) CARAC RERIS I ICAS OF THE SEQUENCE (A) LONG I I UD 6 ammo acids (B) I IPO amino acid (C) FIL? (D) Linear TOPOIOGIA (n) TYPE OF MOI I (ULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID 24 Xaa Asp Asp He Xaa Tip 1 5 0 (2) Information for the identification of sequence number 25 (i) C? RAC I ERIS I ICES OF THE SEQUENCE (A) LONG II UD 6 animo acids (lí) • Or animo acid t (C) FILAMI N 1'ACION unique (D) linear OPOLOGY (ii) TYPE OF MOLECULE. peptide (xi) SEQUENCE DESCRIPTION No Sequence ID.25: Xaa Glu Asp He Xaa Trp I s (2) Information for sequence identification number 26 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH 6 amino acids (B) TTPO amino acid (C) FILAMI N TION, (D) TOPOI OGIA linear (ii) TYPE OF MOI I CULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID.26.

Xaa Arg Asp Xaa lie Trp 1 (2) Information for sequence identification numbers 27 (i) CHARACTERS! ICAS OF THE SEQUENCE (A) LONG II UD 6 animo acids (B) T 1PO amino acid (C) l-IL? MI NI ATION unique (D) lOPol linear OGlA (ii) MOLECULE TTPO: ENCIA peptide: No ID of Sequence: 27: (2) Information for the identification of sequence number: 28: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LONGI TUD: 6 amino acids (B) T PO. amino acid 0 ^ '(C) F1LAM HNTATION: unique (D) TOPOLOGY: linear (ii) TT PO OF MOLECULE: peptide (xi) DESCRI PTION OF SEQUENCE: No of Sequence ID: 28: Xaa Xaa Asp Xaa l ie Trp fifteen # (2) Information for the identification of sequence number: 29: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LONGI TUD: 6 amino acids (B) TTPO. amino acid (C) FILA M ENTATION: unique (D) TOPOLOGY: linear (ii) TT PO OF MOLECULE: peptide (xi) DESCRIPTION i) E SEQUENCE: No of Sequence ID: 29: Xaa Asp Asp Xaa lie Trp (2) Information for sequence identification number: 30: (i) CHARACTERS! ICAS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TTPO amino acid (C) F1LAMENTATION: unique (D) TOPOLOGY: linear lü (TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: No of ID of Sequence: 30: Xaa Glu Asp Xaa lie Trp 1 s (2) Information- for sequence identification number: 3 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FiLAM ENTRY: only 0 (D) TOPOLOGY:; - linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION I > E SEQUENCE: No Sequence ID: 31: Xaa Leu Asp Fe lie Trp (2) Information for the identification of sequence number "52 (i) CHARACTERISTICS OF THE SEQUENCE (A) LONGI1 D 6 animo acids (B) I IPO amino acid (C) FILAMI I ATION (D) IOPOI linear OGIA (n) IO MOI IC ULA peptide (xi) DESCRIPTION DL SEQUENCE No Sequence ID 32? ^ Xaa Xaa Asp le He Tip 1 5 (2) Information for the identification of sequence number 33 (i) CARAC TERIS I ICS OF THE SEQUENCE (?) LONGIIUD 6 animo cides "u! / (B) TYPE of animo acid (C) 1 I LAM I NI ATION unique ( D) IOPOI OGIA linear (n) T IPO OF MOI I (ULA peptide (xi) DI SCRIPTION Di: SEQUENCE No of Sequence ID 33 (2) Information for the id sequence indication number M (i) CHARACTERS I ICAS OF THE SEQUENCE (?) LENGTH '6 amino acids (B) TYPE of amino acid (C) FILAMI NTACIÓN unique (D) TOPO! OR Linear AI (ii) TYPE OF MOI ECULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID.34. , (2) Information for the identification of sequence number 35 (i) CHARACTERISTICS OF THE SEQUENCE (A) LONG II UD 6 animo acids (B) TTPO amino acid (C) FILAMI NT ATION only j ^ (D) IOPOI OG1A linear (ii) TYPE OF MOI ECULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID 35- Xaa Glu Asp Fe lie TTp 1 (2) Information for sequence identification number 36 (i) C? K? Í I CRIS I I. AS OF SEQUENCE (A)! ONGI I l D 6 animo acids t (B) TYPE amino acid (C) FILAM IN TACIÓN unique (D) 10POEOGIA linear (ii) TTPO DE MOI LCULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID.36- Xaa Fe Asp Ee lie Trp 1 • 5 (2) Information for sequence identification number 37 ^ (i) CHARACTERS! ICAS OF THE SEQUENCE (?) LONGIUT) 6 ammo acids (B) TYPE amino acid (C) I IL? MI NT ATION (D) IOPOLOGY linear (ii) TYPE OF MOI I CULA peptide (xi) DI SCRIPTION OF SEQUENCE No Sequence ID 37. (2) Information for the identification of sequence number 3 (i) CHARACTERS I ICAS OF THE SEQUENCE (A) LONGMDD (.Amino acids (B) I IPO animo acid (C) I ILAMI NI ATION unique (D) Linear TOPOLOGY (ii) TYPE OF MOLECULE peptide (xi) SEQUENCE DESCRIPTION 'No Sequence ID- 38: Xaa Xaa Asp He Xaa Xaa 1 5 (2) Information for the identification of sequence number 39 (i) CARAC I? RISTTCAS OF THE SEQUENCE (A) LONGIIDD 6 amino acids (B) TTPO amino acid (C) FIL? Unique MI NT (A) linear TOPOLOGY (ii) ) TYPE DL MOELCUL? peptide (xi) DESCRIPTION DL SEQUENCE No Sequence ID- 39: Xaa Fe Asp He Xaa Tip 1 5 (2) Information for the identification of sequence number 40 (i) CHARACTERS I ICES OF THE SEQUENCE (A) LONGIIUD 5 amino acids (B) I IPO animo acid (C) FILAM1 I ATION unique (D) TOPOI OCIA linear (ii) ) UPO DE MOI I ULA peptide t (xi) SEQUENCE DESCRIPTION: No Sequence ID: 40: Xaa Asp "He Xaa T'rp # 1 5 (2) Information for the identification of sequence number- 41 (i) CHARACTERS TICAS OF THE SEQUENCE (A) LONGI TUD: 6 amino acids (B) TTPO amino acid (C) IT LAME N ATION only * (D) Linear TOPOLOGY ( ii) TYPE OF MOLECULE peptide (xi) SEQUENCE DESCRIPTION: No Sequence ID: 41: Xaa Leu Fe He Xaa Trp É (2) Information for the identification of sequence number 42 (i) CHARACTERS TICAS OF THE SEQUENCE. (A) LENGTH. 6 amino acids (B) TTPO amino acid (C) FILAMI. ONE (D) "Linear TOPOLOGY (ii) TT PO DE MOI LOULA peplido (xi) DE.SCRI PCK) NI) l: SEQUENCE No Sequence ID : 42: Xaa Leu Glu He Xaa T ip # e (2) Information for the identification of sequence number 43 (i) CHARACTERS TICAS OF THE SEQUENCE (A) LONGI TUD 6 amino acids (B) TYPE amino acid (C) F1L? M L N TATION (D) Linear TOPOLOGY (ii) MOTIFUL TTPO 'peptide (xi) SEQUENCE DESCRIPTION No Sequence ID: 43: Xaa Leu Gln He Xaa T? fifteen (2) Information for the identification of sequence number 44 (i) CHARACTERISTICS OF THE SEQUENCE *, (?) LONGI TUD 6 amino acids (B) TYPE amino acid (C) FILA ENT ATION unique (D) T Linear OPOLOGY (ii) ) T IPO DE MOLECULA. peptide (xi) SEQUENCE DESCRIPTION Sequence ID No.: 44: Xaa Leu 'Tu lie Xaa Trp. (2) Information for the identification of sequence number 45 (i) - CHARACTERS "! IC OF THE SEQUENCE # (A) LENGTH> 6 amino acids (B) TTPO amino acid '(C) FILAMENEACION single (D) TOPOI OGIA linear (ii) TYPE OF MOLECULE peptide (xi) DESCRIPTION \) \ l SEQUENCE, No Sequence ID: 45 (2) Information for the identification of sequence number 46 (i) CHARACTERISTICS OF THE SEQUENCE (?) LENGTH 6 amino acids (B) TTPO amino acid fe (C) FIL? MENI? CTON only ^ (D) TOPOI OGIA linear (ii) ) TYPE OF MOLEC ULA peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID- 46: Xaa Leu TTp He Xaa Trp 1 5 (2) Information for the identification of sequence number 47 (i) C? R? CTLRIS I ICAS OF THE SEQUENCE (A) LONGI TUD 6 amino acids (B) 'TYPE - amino acid (C) FIL? MENTATION. unique (D) linear TOPOLOGY (ii) MOLECULE TTPO. peptide (xi) SEQUENCE DESCRIPTION: No Sequence ID: 47: Xaa Leu Asp Val Xaa Trp 1 5 (2) information for the identification of sequence number 48. (i) CHARACTERISTICS OF THE SEQUENCE (?) LONGI TUD 6 amino acids (B) TTPO amino acid (C) FIL? M IN TACIÓN- unique (D) Linear TOPOLOGY fe (ii) TYPE OF MOLECULE peptide (xi) DI SCRI SEQUENCE PCION: No Sequence ID: 48: Xaa Leu Asp Xaa Xaa Trp (2) Information for the identification of sequence number 49. (i) C \ R? (TERI STTC? S GIVE THE SEQUENCE (A) LONGI TUD (.) Amino acids (B) T IPO amino acid. (C) FIL MENTACTION: single - (D) "linear" TOPOLOGY * (ii) TYPE OF MOLECULE, peptide (xi) SEQUENCE DESCRIPTION: No Sequence ID: 49: Xaa Leu Asp Xaa Xaa Trp 1 5 (2) Information for the identification of sequence number 50 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH 6 amino acids (13) TYPE aniino acid (C) FIL? MEN'TACTON. unique (D) linear TOPOLOGY (ii) TI PO OF MOLECULA- peptide (xi) SEQUENCE DESCRIPTION: No Sequence ID: 50 Xaa Arg Asp Xaa Xaa "Trp m 1 5 (2) Information for the identification of sequence number 5 1 (i) CHARACTERISTICS OF THE SEQUENCE (A) LONGI TUD 6 amino acids (B) TI PO amino acid (O) ITE? MENTION. unique (D) TOPOLOGICAL A. linear (ii) TYPE OF MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID: 51: Xaa Lis Asp Xaa Xaa Tip (2) Information for the identification of sequence number 52 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH (.amino acids (B) TYPE amino acid (C) FIL? MENIACTON only (D) TOPOLOGY linear (ii) TYPE OF MOLECULE peptide (xi) SEQUENCE DESCRIPTION No Sequence ID: 52: Xaa Xaa Asp Xaa Xaa Trp (2) Information for the identification of sequence number 53 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH 6 amino acids (B) TTPO amino acid (C) F1LAMENIACI N only (D) TOPOLOGY linear (n) I IPO DE < H.I (II? Peptido (xi) 1) 1 SCRIPTION OF SL CUENCT? No Sequence ID 53- Xaa Asp Asp Xaa Xaa Trp (2) Information for the identification of sequence number 54 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH 6 amino acids (B) TYPE animo acid (C) PHILAN I IN T ATION unique (D) TOPOLOGY 'linear (ii) TYPE MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE No Sequence ID: 54: Xaa Glu Asp Xaa Xaa Ti p 1 5 (2) Information for the identification of sequence number 55 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH 6 amino acids (B) TYPE ammo acid (C) FIL? MENTATION only (D) TOPOLOGY linear (ii) TI PO DE MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID. 55 1 5 (2) Information for the identification of sequence number: 56 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH 6 amino acids (B) TYPE amino acid (C) FIL? MEN'TACTON only (D) TOPOLOGY- linear (ii) TT PO OF MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE. No Sequence ID: 56: , i ^? Xaa Leu Asp Fe Xaa Trp 1 5 (2) Information for the identification of sequence number 57 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH- 6 amino acids fe (B) TTPO amino acid (C) F1LAMEN TATION only (D) Linear TOPOLOGY (ii) T IPO OF MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE. No Sequence ID: 57: Xaa Xaa? Sp Fe Xaa TTp (2) Information for the identification of sequence number ^ f (i) ISTK CHARACTER AS DÉLA SEQUENCE (A) LENGTH '6 amino acids v5? (B) amino acid TYPE (C) FLLAMENIATION unique (D) linear TOPOLOGY (li) 'I IPO MOLECULE peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID 58- (2) Information for the identification of sequence number 59 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH (.amino acids (B) TTPO amino acid 5 (C) FIL? MENTAC1ON only faith (D) TOPOLOGY linear (ii) TTPO DE MOLECULA peptide (xi) SEQUENCE DESCRIPTION Sequence ID No. 59 Xaa Asp Asp Fe Xaa T? 0 1 5 (2) Information for the identification of sequence number 60 (i) C ARACTERISTIOAS OF THE SEQUENCE (\) LON < d 1 l D (.amino acids (B) TTPO amino acid (C) FILAMENTATION: unique (D) TOPOLOGY: linear (Ü) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: No Sequence ID: 60: Xaa Glu Asp Fe Xaa Trp 1 (2) Information for sequence identification number 61 - (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH: 6 amino acids (B) 'TYPE amino acid (C) FILA MENTATION: unique (D) TOPOLOGY: linear (ii) "TYPE OF MOLECULE, peptide (xi) SEQUENCE DESCRIPTION: No Sequence ID: 61: Xaa Fe Asp Fe Xaa Trp 1 5 (2) Information for the identification of sequence number 62 (i) CHARACTERISTICS OF THE SEQUENCE (A) LENGTH: 6 mood acids (13) TTPO amino acid (C) FIL? \ INITIA TION (D) TOPOLOGY: linear f ( ii) TYPE OF MOLECULE peptide (xi) SEQUENCE DESCRIPTION. No Sequence ID: 62: Xaa Arg Asp Fe Xaa Ti p 1 5 (2) Information for sequence identification number 63 (i) SEQUENCE CHARACTERISTICS (A) LENGTH '6 animo cidos ™ (B) TYPE amino acid (C) FLLAMEN TATION unique (D) TOPOLOGY. linear (ii) TYPE OF MOLECULE. peptide (xi) DESCRIPTION OF SEQUENCE No of Sequence ID. 63. Xaa Leu Asp Fe Xaa Trp (2) Information for sequence identification numbers 64 (i) SEQUENCE CHARACTERISTICS (A) LENGTH 6 animo acids (B) TYPE animo acid (C) FIL? MEM "ATION unique (D) TOPOLOGY linear (ii) II PO FROM M (> LE (ULA pepudo (xi) DESCRIPTION OF SEQUENCE: No of Sequence ID: 64:

Claims (15)

1. CLAIMS where AA1 is Seq ID number. wherein R is hydrogen, * V alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, fluorenylmethyl, • N-R R- wherein R2 and R2 are each the same or different and each is hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl, "cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, O -C-OR, wherein R is as defined above, -OR2, wherein R2 is as defined ai i iba, O -NCNR, wherein R and R are as defined R2 above, O -C-C (R9) 3, where R "is F, Cl, B? Or 1, -CH2-OR2, where R2 is as defined above, or N-C-R, where R is hydrogen or alkyl R 2A and R is as defined ai 1 was O -N-C-OR3, where R A and R ^ are or were defined above excluding R is hydrogen or O -C-H-R 2, where R is as defined 1 i was, I Rl is hydrogen or alkyl, Z is ) m, where m is cei oo an integer or 1 or 2, n where R2 is as defined above - (CH2) "-, where n is wax or an integer of 1, 2, 3 or 4, - ( CH2) n-CH = CH- (CH2) n -, where n and n 'are each independently the same or different and each as defined above for n, CR -, where R and R are as defined OR2 above or R2 5 -C-, where R2 and R3 are each the same or different ^ -R I. and each is as defined above, X and Y are the same and substituted in the same position on the aromatic chain and each can to be 1, 2, 3 or 4 elective substitutes from the group consisting of hydrogen, or halogen, alkyl, -CO2R2, wherein R2 is as defined above, -CONR2, wherein R2 and IV are as defined by I. 'ai nba, -NR2, where R2 and R' are as defined k- above or nitro or where R, Z, X and Y are as defined ai i iba. wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroapl, -N-R3B, wherein R2b and IV1 'are each the same or 2b or different and each is hydrogen, alkyl, cycloalkyl, apl or heteroapl, -OR2b, wherein R2b is as defined above OR CN-R3b, wherein R2b and IV1 'are each the same and each is R2b as is defined .11 riba for R2b and IVb, * 0 O-C 11 -R », where R is co or defined above NH-NH • -C i'-NH-R _, where IV is as defined above or O 5 -C-OR2b, where R2b is co or is defined ap iba and R 'and n are as defined above or 9A2 is absent. Or R1 wherein W is -CI- or -C'-, R 'R' is hydrogen, alkyl, aryl, heteroaryl, wherein R2b and R3b are each the same or different and each is as defined above, O 0 * -C-R b, wherein R, 22bD is as defined above or wherein R2b is as defined above and R1 and n are as defined above or AA3 is absent, 5 AA4 and AA5 are each independently absent or each is independently 0 where R6 is hydrogen. alkyl, alkenyl, alkynyl, ai or heteroaryl and R and n are as defined above; AA6 is wherein R is aryl or heteroaryl, Rs is O -C 11 -OR 1, wherein R 1 is as defined above, -OR 1, wherein R 1 is as defined above, O -C HNR,, wherein R is as define R1 arnba or -CH2-OR ', where R1 is as defined above and R' and n are as defined above, * The stereochemistry at C cn AA1-AA2-AA3-AA4o-AA5 is D, L or DL and the stereochemistry at C in AA6 is L, or a pharmaceutically acceptable salt thereof.
2. 2 A compound according to Claim 1, wherein AA is wherein R * and R are each the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl apl, arylalkyl heteroanl, fluorenylmethyl. O -N-C l? -N-R. , where R and R are as defined R2 R2 above, OR II -C-C (R9) 3, wherein R < is F, Cl, B? or 1, -NH-C-R3, wherein R3 is as defined above or wherein R3 is as defined above excluding R 'is hydrogen, Z is -O-, -S (O) m, where m is cei or an integer or 1 or 2, wherein R2 is as defined above • ( CH2) ,, -, where n is cei or an integer of l, 2, 3 or 4, i Uti? ' - (CH2) "- CH = CH- (CH2)" - where n and n 'are each independently independent or equal and each co or is defined before for n, -CH-, wherein R1 is hydrogen or alkyl OR1 _ ^ j R¿ -C-, where R and R are each the same or different -R I. ' and each is as defined above and 0 X and Y are the same and substituted in the same position on the aromatic chain and each substitute is selected from the group consisting of Indi ogeno, halogen or alkyl, AA2 is wherein R 4 is hydrogen, alkyl, alkenyl, 4-alkynyl, cycloalkyl, aryl, heteroaryl, -N-R 3B, wherein R 2 and R '1' are each the same or different and each is hydrogen , alkyl, cycloalkyl, anl or heteroapl, -OR2b, wherein R2b is as defined above OR II -C-N-R, h, wherein R 2 > is how i was defined as R2b where R 'and IV are each the same or different and each is as a for R2b and IVb, C-R \ where R is as defined above NH II, 2b NH-C-NH-R ', wherein R' is as defined above or O -C-OR2'1, wherein R2b is as defined above and R1 and n are as defined above or AA is absent, l oo ^ "AA3 is or IV where VV is -C- or IV R5 is apl heteroaryl 0 -NR ", where R 'and R-" are each R' i "i? al or different v each is as defined above, OR CR, where IV is as defined above or O -C-OIV. in Junde R2 'is as defined above and R and n are as indicated above or A A "' is absent. 5 AA and AA 'are each independently absent or each is independently OR II wherein IV is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl v! R1 and n are as defined above; AA 'is where R is aryl or heteroai il \ R1 and n are e cnio defined above or where R, R1 and n are as defined above, The stereochemistry in C in AA1-AA2-AA3-AA4o-AA5 is D, L or DL and the + stereochemistry in C in AA6 is L or a pharmaceutically acceptable salt thereof.
3. 3. A compound according to Claim 2, wherein AA1 is where R is wherein R and R are each the same or different and each is hydrogen, alkyl, apl or lluoyl enylmethyl, or I-N-C-N-IV, wherein R 2 and IV are as defined R RR above. * r-C-C (R9) 3, where R9 is F, Cl, Bi or I, where R3 is as sc defined above or or II NH-C-OR111, wherein Rll) is hydrogen, alkyl, aryl, arylalkyl, or lucloylmethyl, G ^ excluding R is hydrogen, Z is -OR-, -S- -NH-, - (CH2) "-, where n is cei or an integer of 1, 2, 3 or 4 or ", - (CH2)" a-CH = CH- (CT E) ",. r, where na and n'1" 'are each in a way & independent equal or different and each one is zero or an integer of I or 2 and X and Y are equal and substituted in the same position on the aromatic chain and each substitute is chosen from the group consisting of hydrogen, halogen or I rent, AA2 is O * II -N CH-C- f? < I Rl < CH2) n R4 wherein R1 is hydrogen or methyl, R4 is hydrogen alkyl, aryl, heteroaryl, -NR, 1 !, wherein R by IV1 'are each the same or R, 2b or different and each is hydrogen or alkyl , OR II C-N-R, wherein R and R are each the same and each is hydrogen or alkyl, Or -C-R21 ', wherein R2b is as defined above NH-NH-C-NH-R21', wherein | V 'is as defined above or O -C-OR21', wherein R2b is as define arnba and n is zero or an integer of 1, 2, 3 or 4 or AA2 is absent, AA3 is * -HN CH-W-, IV (CH2) n OR R1 * where W i 2S -C II- 0, -c 1-, 1, R5 is aril, heteroaryl, OR -C 'i-NHR,, b, wherein R31 1 is hydrogen or alkyl KT O 1 I -C-R2b, wherein R2b is hydrogen or alkyl or OR -C-OR21 ', wherein R2b is hydrogen or alkyl and R1 and n are as defined above, 5 AA4 and AA5 are each independently # 0 where R6 is hydrogen, I rent, cycloalkyl or apl and R and n are as defined above, where R7 is aril or hetei oai íl and R1 and n are as defined ai i iba o where R, 7, R, R and n are as defined above, The stereochemistry in C in AA-AA-AA A 3-AA or-AA is D, L or DL and the stereochemistry in C in AA6 is L or a pharmaceutically acceptable salt thereof.
4. 4 A compound of compliance with Claim 3 chosen from the group consisting of L-Bhg - Le -Asp - lie - lie -Trp; Seq ID No D- Bhg- Leu -Asp- lie- lie -Trp; Seq ID No Ac - L- Bhg - Leu -Asp- lie- Ile-Trp; Seq ID No Ac -D-Bhg -Leu -Asp- lie -lie- Trp; Seq ID No 2 Ac - D - Bhg - Orn - Asp - II e - II e - Trp; Seq ID Ho 3 S: -D-B g -Lys -Asp- lie -lie -Trp; Seq ID No 4 c -D-Bhg- Asp - Aspilae -Trp; Seq ID No 5 Ac -D-Bhg -Glu -Asp- lie- Ile-Trp; Seq ID lio 6 Ac-D-Blig-Phe-Asp-Ile-Ile-Trp; Seq ID No 7 Ac -D-Bhg -Arg -Asp -lie -lie- Trp; Seq ID No 8 Ac-D-Bhg -Asp- li -lie -Trp; Seq ID No 9 Fmoc - D - Bhg - Leu - Asp - II e - He - Trp; Seq ID No 2 Fmoc -D-Bhg- Orn-? Sp-lie -lie- Trp; Seq ID No 3 Fmoc -D-Bhg -Lys -Asp- lie -lie -Trp; Seq ID No 4 Fmoc - D - Bhg -? Sp -Asp -lie- He- Trp; Seq ID No 5 Fmoc -D-Bhg -Glu-? Sp- He -He- Trp; Seq ID No 6 ÍTICO P -Bhg -Phe -Asp -lie -lie -Trp; Seq ID No 7"Fmoc -D-Bhg -Arg-Asp- He -He -Trp; Seq ID or 8 Fmoc -D-Dhg-Asp- lie -lie -Trp; Seq ID No 9 Ac -D-Bhg -Leu -Phe -lie -lie- Trp; Seq ID No 10? C -D-Bhg -Leu- snile -lie -Trp; Seq ID No 11? C - • D-Bh -Leu- Gluelie -lie- Trp; Seq ID No 12 Ac -D-Bhg -Leu-Gln- lie- Ile-Trp; Seq ID No 13 Ac-D-Bhg-Leu-Tyr-Ile-He-Trp; Seq ID No 14? C -D -Bhg- Leu -I-Nal -Hele- Trp; Seq ID No 15 Ac -D-Bhg- Leu- 2 -Nal -lie -lie- Trp; Seq ID No 15 -D-Bhg -Leu -Trp- lie -lie- Trp; Seq ID No 16 cD - Bhg - Leu -Asp-Val - He - Trp; Seq ID No 17 Ac-D-Bh -Leu -As -lie -Val -Trp; Seq ID No 18? c - D - Bhg - Leu - As - Chx - I le - Tr; Seq ID No 19? C - D - DIKJ - Leu - Asp - He - Chx - Trp; Seq ID No 20? C - D - Bhg -? Rg -Asp - He - CT ÍC- Trp; Seq ID No 21 Ac - D - Bhg - Lys -Asp - He - Chx - Trp; Seq ID No 22? C - D - Ehg - Orn - Asp - He - Chx - Trp; Seq ID No 23? CD-Bhg-? Sp-Asp-He-Chx-Trp; S q ID No 24 Ac-D-Lpg-Glu-Asp-He-Clix-Trp; Seq ID No 25 Fpioc - D - Phq - Leu - Phe - He - He - Trp; Seq ID No 10 Fmo c-3) - riig-1? u - As n - He - H e - Trp; .x '-' i ID No 11 End --- f "rll j -Leu-Glu- Ilc-Ile-Trp; í. '» q ID No 12 I went "' i'ljj r. u-Gln-Ile-He-Trp; S "-q ID No 13 Fmoc-D-Bhg-Leu-Tyr-He-Ile-Trp; seq ID O: 14 J ^ Fmoc-D-Bhg-Leu-Asp-Val-Ile-Trp; seq ID: 17 9 Fmoc-D-Bhg-Leu-Asp-He-Val-Trp; Seq ID NO: 18 Fmoc-D-Bhg-Leu-Asp-Chx-Ile-Trp; seq ID NO: 19 Fmoc-D-Bhg-Arg-Asp-Chx-Ile-Trp; seq ID NO.- 26 Fmoc-D-Bhg-Lys-Asp-Chx-Ile-Trp; seq ID NO: 27 Fmoc-D-Bhg-Orn-Asp-Chx-Ile-Trp; seq ID NO: 28 Fmoc-D-Bhg-Asp-Asp-Chx-Ile-Trp; seq ID KO: 29 Fmoc-D-Bhg-Glu-Asp-Chx-He-Trp; seq ID No: 30 Fmoc-D-Bhg-Leu-Asp-He-Chx-Trp; seq ID O: 20 Fmoc-D-Bhg-Arg-Asp-Ile-Chx-Trp; seq ID NO: 21 Fmoc-D-Bhg-Lys-Asp-He-Chx-Trp; seq ID NO: 22 ^ JP ^ Fmoc-D-Bhg-Orn-Asp-Ile-Chx-Trp; Seq ID NO: 23 ^ Fmoc-D-Bhg-Asp-Asp-Ile-Chx-Trp; Seq ID O: 24 Fmoc-D-Bhg-Glu-Asp-He-Chx-Trp; Seq ID NO: 25 Ac-D-Bheg-Leu-Asp-He-He-Trp; seq ID NO: 2 Ac-D-Bheg-Om-Asp-Ile-He-Trp; Seq ID O: 3 Ac-D-Bheg-Lys-Asp-He-He-Trp; Seq ID NO.- 4 Ac-D-Bheg-Asp-Asp-He-He-Trp; Seq ID O: 5 Ac-D-Bheg-Glu-Asp-Ile-He-Trp; seq ID O.- 6 Ac-D-Bheg-Phe-Asp-Ile-He-Trp; seq ID NO: 1 Ac-D-Bheg-Arg-Asp-He-He-Trp; Seq ID NO: 8 Ac-D-Bheg-Asp-He-He-Trp; Seq ID NO: 9 MmFmoc-D-Bheg-Leu-Asp-He-He-Trp; Seq ID NO: 2 Fmoc-D-Bheg-Orn-Asp-He-He-Trp; Seq ID O: 3 Fmoc-D-Bheg-Lys-Asp-He-Ile-Trp; Seq ID NO: Fmoc-D-Bheg-Asp-Asp-He-Ile-Trp; Seq ID NO: 5 Fmoc-D-Bheg-Glu-Asp-He-Ile-Trp; Seq ID O: 6 Fmoc-D-Bheg-Phe-Asp-He-Ile-Trp; Seq ID NO: 1 Fmoc-D-Bheg-Arg-Asp-He-He-Trp; 'Seq ID O.- 8 Fmoc-D-Bheg-Asp-He-He-Trp; Seq ID NO: 9 Ac-D-Bheg-Leu-Phe-Ile-Ile-Trp; Seq ID O: 10 c-D-Bheg-Leu-Asn-He-Ile-Trp; Seq ID NO: 11 Ac-D-Bh g-Leu-Glu-Ile-He-Trp; Seq ID NO: 1? ? c- D- h g-I.eu-Gln-Ile-Ile-Trp; Seq ID NO: IJ ? c-D-r.h ^ 'í Le -Tyr-lie-lie-Trp; s? q ID HO: i ' Ac-D-Bl. < q- Leu-l-Nal-Ile-Ile-Trp; Seq ID No-. Ac-D-Bheg-eu-2-Nal -lie-Lie-Trp; Seq ID No: 15 Ac-D-Bheg-Leu-Trp-He-He-Trp; Seq ID No: 16 fAc-D-Bheg-Leu-Asp-Val-Ile-Trp; Seq ID No: 17 Ac-D-Bheg-Leu-Asp-lie-Val -Trp; Seq ID No: 18 Ac-D-Bheg-Leu-Asp-Chx-He-Tr; Seq ID No: 19 Ac-D-Bheg-Leu-Asp-lie-Chx-Trp; Seq ID No: 20 Ac-D-Bheg-Arg-Asp-He-Chx-Trp; Seq ID No: 21 Ac-D-Bheg-Lys-Asp-He-Chx-Trp; Seq ID No: 22 Ac-D-Bheg-Orn-Asp-He-Chx-Trp; Seq ID No: 23? C-D-Bheg-Asp-Asp-Ile-Chx-Trp; Seq ID No: 24 Ac-D-Bheg-Glu-Asp-IIe rChx-Trp; Seq ID No: 25 Fmoc-D-Bheg-Leu-Phe-Ile-Ile-Trp; Seq ID No: 10 Fmoc-D-Bheg-Leu-Asn-He-He-T £ p; Seq ID No: 11 Fmoc-D-Bheg-Leu-Glu-He-He-Trp; Seq ID Mo: 12 Fmoc-D-Bhe -Leu-Gln-lie-lie-Trp; Seq ID No: 13 Fmoc-D-Bheg-Leu-Tyr-IIe-IIe-Trp; Seq ID No: 14 Fmoc-D-Bheg-Leu-Asp-Val-He-Trp; Seq ID No: 17 Fmoc-D-Bheg-Leu-As -lie-Val -Trp; Seq ID No: 18 Fmoc-D-Bheg-Leu-Asp-Chx-He-Trp; Seq ID No: 19 Fmoc-D-Bheg-Arg-Asp-Chx-He-Trp; Seq ID No: 26 Fmoc-D-Bheg-Lys-Asp-Chx-lie-Trp; Seq ID No: 27 Fmoc-D-Bheg-Orn-Asp-Chx-He-Trp; Seq ID No: 28 Fmoc-D-Bheg-Asp-Asp-Chx-He-Trp; Seq ID No: 29 F uc-D-Bheg-Glu-Asp-Chx-He-Trp; Seq ID No: 30 Fmoc-D-Bheg-Leu-Asp-He-Chx-Trp; Seq ID No: 20 Fmoc-D-Bheg-Arg-Asp-lie-Chx-Trp; Seq ID No: 21 Fmoc-D-Bheg - Lys-? Sp-He-Chx-Trp; Seq ID No: 22 Fpioc-D-Bheg-Orn-Asp-He-Chx-Trp; Seq ID No: 23 Fmoc-D-Bheg-Asp-Asp-He-Chx-Trp; Seq ID No: 24 Fmoc-D-Bheg-Glu-Asp-He-Chx-Trp; Seq ID No: 25 Ac-D-Txg-Leu-? Sp- He-He-Trp; Seq ID No 2 Ac-D-Txg -Orn-? Sp-lie-lie-Trp; Scq ID No 3? C-D- Txg-Lys -? S - 11e- He-Trp; Seq ID No 4? C- D-Txg-Asp-Asp-11e-11 -Trp; Soq ID No 5? C - - T: j -G1u -? Sp- 11c -He- Tr; :: • - ( { L l) lio 6? O - D - T. j - Pl? E -? Sp - He - He - Trp; S ID lio 7? C-D-UHq -? .- g? Sp- He- He -Trp; VQ .TD No 8 n Ac-D-Txg-Asp-Ile-Ile-Trp; Seq ID? 9 X Fmoc -D-Txg -Leu-Asp-lie -lie- Trp; Seq ID? O 2"moc -D-Txg -Orn- Asp- He -He -Trp; Seq ID? O 3 Fmoc -D-Txg -Lys -Asp- lie- lie- Trp; Seq ID? O 4 Fmoc- D-Txg -Asp- Asp- lie -lie -Trp; Seq ID? O 5 Fmoc -D-Txg- Glu-Asp- lie -lie- Trp; Seq ID? O 6 Fmoc -D-Txg- Phe -Asp- Hele-Thrp; Seq ID? 7 Fmoc-D-Txg-Arg-Asp-He-Ile-Trp; Seq ID? 8 Fmoc-D-Txg-Asp-Ile-He-Trp; Seq ID? 9 Ac -D-Txg- Leu- Phe -lie -lie -Trp; Seq ID? O 10 Ac -D-Txg- Leu- Asn- lie -lie -Trp; Seq ID? O 11 Ac-D-Txg-Leu -Glu-Ile-He-Trp; Seq ID? O 12 Ac-D-Txg-Leu-Gln-Ile-He-Trp; Seq ID? O 13? 'C -D-Txg -Leu- Tyr -He- He -Trp; Seq ID? Or 14 Ac-D-Txg-Leu-1-Nal-He-Ile-Trp; Seq ID? O lb Ac-D-Txg-Leu-2-Nal-He-He-Trp; Seq ID # 15 Ac -D-Txg- Leu- Trp- lie- Ile-Trp; Seq ID? O 16 Ac -D-Txg- Leu-Asp -Val- Ile-Trp; Seq ID? O 17 Ac -D- Txg-Leu-Asp-lie -Val -Trp; Seq ID? O 18 Ac -D-Txg -Leu-Asp- Chx- lie -Trp; Seq ID? O 19 Ac -D-Txg- Leu-Asp -lie- Chx- Trp; Seq ID? 20 Ac -D-Txg- Arg- Asp -He- Chx-Trp; Seq ID? 21 Ac-D - Txg -L s - Asp -He- Chx- Trp; Seq ID ? or 22 -D -Txg- Orn- Asp- He- Chx-Trp; Seq ID? Or 23? C -D-Txg-Asp-Asp-lie-Chx-Trp; Seq ID 24 Ac -D-Txg-Glu -Asp- lie- Chx-Trp; Seq ID? O 25 Fmoc -D-Txg- Leu -Phe -He -He- Trp; Seq ID? O 10 Fmoc -D-Txg -Leu -Asn- lie -lie -Trp; Seq ID? O 11 Fmoc -D-Txg- Leu-Glu lie -lie -Trp; Seq ID? 12 Fmoc -D-Txg -Leu-Gln- He -He -Trp; Seq ID 13 o Fmoc - D - Txg - Leu - Tyr - He - He - Trp; Seq ID? Or 14 Fmoc -D-Txg- Leu -Asp-Val -li -Trp; Seq ID 17 Fmo c-D - Txg - Leu - Asp - II e - Val - Trp; Seq ID? O - 3 Fmsc - D - Txg - Leu -? Sp - Chx - He - Trp; Seq ID? O Jn Fmo c-D - rJ 'x g - Arg - Asp - Clix -He- Trp; Seq ID? O Fmo c-D- and g-Lys-Asp-Chx -He- Trp; Seq ID? S Fmoc - D - Txg - Orn -? Sp - Chx -He- Trp; Seq ID? O Fmoc - D - Txg - 7vsp - Asp - C ix - He - Trp; Seq ID No: 29 - ^ taoc - D - Txg - Glu - Asp - Chx - Ile - Trp; Seq ID No: 30 -D- Txg -Leu -Asp- He-Chx- Trp; Seq ID No: 20 Fmoc-D-Txg-Arg-Asp-He-Chx-Trp; Seq ID No: 21 Fmoc-D-Txg-Lys-Asp-He-Chx-Trp; Seq ID No: 22 Fmoc-D-Txg-Orn-Asp- He-Chx-Trp; Soq ID No: 23 Fmoc-D-Txg-? Sp-Asp-He-Chx-Trp; Seq ID No: 24 Fmoc-D-Txg-Gl-Asp-He-Chx-Trp; Seq ID No: 25 E-D-Bhg-Leu-Asp-lie-lie-Trp; Seq ID No: 2 Bz-D-Bhg-Leu-Asp-lie-lie-Trp; Seq ID No: 2 Pya-D-Bhg-LOu-As? -Ile-Ile-Tr ?; Seq ID No: 2 Cxi -D-Bhg-Leu-Asp-lie-lie-Trp; Seq ID No: 2 - ^ da - D - Bhg - Leu - Asp - IIe - IIe - Trp; Seq ID No: 2 ffx.1 (U) -D-Bhg-Leu-Asp-He-He-Trp; Seq ID No: 2 Me (U) -D-Bhg-Leu-Asp-He-He-Trp; Seq ID No: 2 tBu-D-Bhg-Leu-Asp-He-He-Trp; Seq ID No: 2 CF3CO-D-Bhg-Leu-Asp-lie-Ile-Trp; Seq ID No: 2 Et-D-Bheg-Leu-Asp-liele-Trp; Seq ID No: 2 Bz-D-Bheg-Leu-Asp-Ile-Ile-Trp; Seq ID No: 2 Pya-D-Bheg-Leu-Asp-He-He-Trp; Seq ID No: 2 Cxi -D-Bheg-Leu-Asp-He-He-Trp; Seq ID No: 2 Ada-D-Bheg-Leu-Asp-lie-lie-Trp; Seq ID No: 2 Cxi (U) -D-Bheg-Leu-Asp-Ile-He-Trp; Seq ID No: 2 ^ B (U) -D-Bheg-Leu-Asp-He-He-Trp; Seq ID No: 2 tBu-D-Bheg-Leu-Asp-lie-lie-Trp; Seq ID No: 2 CF3CO-D-Bheg-Leu-spie-Ile-Trp; Seq ID No: 2 Ac-D-Bhg-Leu-Asp-he-He-Trp; Seq ID No: 31 Ac-D-Bh -Orn-Asp- Phe-He-Trp; Seq ID No: 32 Ac-D-Bhg-Lys-Asp-Phe-He-Trp; Seq ID No: 33 Ac-D-Bh -Asp-Asp-Phele-Trp; Seq ID No: 34 Ac-D-Bhg-Glu-Asp-Phe-He-Trp; Seq ID No: 35 ? c-D-Bhg -Phe-? sp- Phe-lie-Trp; Scq ID No: 36 Ac-D- Bíg-Arg-? Sp- Phe-Ile-Trp; Seq ID No: 37 ? c - D - P.it g - Leu-Asp - Phe - He -Trp; Seq ID No: 31 ? c - D - Bh'-j - Ovn -? '-.p - Phe - lie -Trp; ID No: 32 ? c -D-r?] c-l.ys -? -; p - Phe -He-Trp; Seq ID No: 33 ? c -D - "h g -? sp-A5.p - Phe- He -Trp; Soa ID No: 34 Ac-D-Bheg-Glu-Asp-Phe-Ile-Trp; Seq ID No 35 Ac-D-Bheg-Phe-Asp-Phe-lie-Trp; Seq ID No. 36 I ^ Lc-D-Bheg-Arg-Asp-Phe-He-Trp; Seq ID No 37 ^ L-B g-Leu-Asp-lie-N-Melle-Trp; Seq ID No 20 D-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No 20 Ac-L-Bhg-Leu-Asp-lie-N-Melle-Trp; Seq ID No 20 Ac-D-Bhg-Leu-Asp- He-N-Melle-Trp; Seq ID No 20 Ac-D-Bhg-Orn-Asp-Ile-N-Melle-Trp; Seq ID No 38 Ac-D-Bhg-Lys-Asp-lie -? - Melle-Trp; Seq ID No 22 Ac-D-Bhg-Asp-Asp-lie -? - Melle-Trp; Seq ID No 24 Ac-D-Bhg-Glu-Asp-Ile-N-Melle-Tr; Seq ID No 25 Ac-D-Bhg-Phe-Asp-He-? - Melle-rp; Seq ID No 39 Ac-D-Bhg-Arg-Asp-He -? - Melle-Trp; Seq ID No 21"g ^ c-D-Bhg-Asp-Ile -? - Melle-Trp; Seq ID No 40 ^ moc-D-Bhg-Leu-Asp-Ile -? - Melle-Trp; Seq ID No 20 F oc-D-Bhg-Orn-Asp-He -? - Melle-Trp; Seq ID No 38 Fmoc-D-Bhg-Lys-Asp-He -? - Melle-Trp; Seq ID No Fmoc-D-Bhg-Asp-As -lie -? - Melle-Trp; Seq ID No 24 Fmoc-D-Bhg-Glu-Asp-lie -? - Melle-Trp; Seq ID No 25 Fmoc-D-Bhg-he-Asp-lie -? - Melle-Trp; Seq ID No 39 Fmoc-D-Bhg-Arg-Asp-Ile-N-Melle-rp; Seq ID No 21 Fmoc-D-Bhs-Asp-He -? - Melle-Trp; Seq ID No 40 Ac-D-Bhg-Leu-Phe-He -? - Melle-Trp; Seq ID No 41 Ac-D-Bhg-Leu-Gln-He-? - Melle-Trp; Seq ID No 43 Ac-D-Bhg-Leu-Tyr-He -? - Melle-Trp; Seq ID No 44 Ac-D-Bhg-Leu-1-Nal-Ile-N-Melle-rp; Seq ID No 45 Ac-D-Bhg-Leu-2-Nal-Ile-N-Melle-Trp; Seq ID No 45 Ac-D-Bhg-Leu-Trp-Ile-N-Melle-Trp; Seq ID No 46 Ac-D-Bhg-Leu-Asp-Val-N-Melle-Trp; Seq ID No 47 Ac-D-Bhg-Leu-Asp-He-N-MeVal-Trp; Seq ID No 20 Ac-D-Bhg-Leu-Asjn-Chx-N-Melle-Trp; Seq ID No 48 Ac-D - Bhg - Leu -? Sp - He - N - MeChx - Trp; Seq ID No 20 Ac - D Bhg - A rg -? Sp - II e - N - MeClix - Trp; Seq ID No ? c - D- Bhg - Lys -? sp •• Ile-N-MeChx- Trp; Seq ID No ? c-D-B q -Orn-? s - lie-N-MeChx-Tr; Seq ID No 3fl or Ac-D-Bhg-Asp-Asp-Ile-N-MeChx-Trp; Seq ID No: 24 Fmoc -D-Bhg-Leu-Gl-He-N-Melle-Trp; Seq ID NO: 42 Fmoc-D-Bhg-Leu-Gln-Ile-N-Melle-Trp; Scq ID No: 43 Fmoc-D-Bhg-Leu-Tyr-Ile-N-Melle-Trp; scq ID NO: 44 Fmoc-D-Bhg-Leu-sp-Val-N-Melle-Trp; seq ID NO: 47 Fmoc-D-Bhg-Leu-sp-He-N-MeVal-Trp; seq ID NO: 20 Fmoc-D-Bhg-Leu-Asp-Chx-N-Melle-Trp; seq ID NO: 49 Fmoc-D-Bhg-Arg-Asp-Chx-N-Melle-Trp; Seq ID NO: 50 Fmoc-D-Bhg-Lys-Asp-Clix-N-Melle-Trp; Seq ID NO: 51 Fmoc -D-Bhg -Orn- Asp-Chx -N-Melle -Trp; Seq ID NO: 52 D-Bhg-? Sp-Asp-Chx-N elle-Trp; SEQ ID O: 53 D-Bhg-Glu-Asp-Clix-N-Melle-Trp; seq Uncle ID: 54 Fmoc-D-Bhg-Leu-Asp-He-N-MeClix-Trp; Seq ID O: 20 Fmoc-D-Bhg-? Rg-Asp-Ile-N-MeChx-Trp; seq ID NO: 21 Fmoc-D-Bhg-Lys-Asp-Ile-N-MeChx-Trp; Seq ID NO: 22 B'moc-D-Bhg-Orn-Asp-He-N-MeChx-Trp; Seq ID NO: 38 Fmoc-D-Bhg-Asp-Asp-Ile-N-MeChx-Trp; Seq ID NO: 24 Fmoc-D-Bhg-Glu-Asp-He-N-MeChx-Trp; Seq ID NO: 25 Ac-D-Bh'-g-Leu-Asp-Ile-N-Melle-Trp; seq ID O: 20 Ac-D-Bheg-Orn-Asp-He-N-Melle-Trp; Seq ID O: 38 c-D-Bheg-Lys-Asp-Ile-N-Melle-Trp; Seq ID O.- 22 * Ac-D-Bheg-Asp-Asp-He-N-Melle-Trp; Seq ID NO: 24 Ac-D-Bheg-Glu-Asp-He-N-Melle-Trp; Seq ID NO: 25 c-D-Bhcg-Phe-Asp-He-N-Melle-Trp; Seq ID NO: 39 Ac-D-Bheg-Arg-Asp-He-N-Melle-Trp; Seq ID NO: 21 Ac-D-Eheg-Asp-He-N-Melle-Trp; Scq ID NO: 40 Fmoc-D-Bheg-Leu-Asp-He-N-Melle-Trp; Seq ID NO: 20 Fmoc-D-Bheg-Orn-Asp-He-Melle-Trp; Seq ID NO: 38 Fmoc-D-Bheg-Lys-? Sp-He-N-Melle-Trp; Seq ID lio-, 22 Imoc-D-Bheg-? Sp-Asp-Ile-N-Melle-Trp; Scq. ID NO: 24 Fiuoc • D-l.hcg-Glu-? Sp-Ile-N-McIle-Trp; ñ q ID No: 25 Fmoc-D-Bh ^ q-Phe-? S-p-Ile-N-Melle-Trp; s-p ID ua-. 39 J) i-or; -r-B) "q-7-rg-? Sp-Ile-N-Melle-Trp; s-q ?? IÍO: 21 Fi'I C-D Plir-g -? Sp -U O-N-Melle-Trp; -a -.- No: 40 . Ac-D-Bheg-Leu-Phe-Ile-N -Melle-Trp, Seq ID No: 41 Ac-D-Bheg-Leu-Asn-He-? -Melle-Trp, Seq ID No: 55 Go Ac-D-Bheg-Leu-Glu-Ile-? -Melle-Trpi Seq ID No: 42 Ac-D-Bheg-Leu-Gln-He-? -Melle-Trp, Seq ID No: 43 Ac-D-Bheg-Leu-Tyr-He-? -Melle-Trp; Seq ID No: 44 Ac-D-Bheg-Leu-1-Nal-He • N-Melle-Trp; Seq ID No: 45 Ac-D-Bheg-Leu-2-Nal-He-N-Melle-Trp; Seq ID No: 45 Ac-D-Bheg-Leu-Trp-He-N • Melle-Trp; Seq ID No: 46 Ac-D-Bheg-Leu-Asp-Val-N -Melle-Trp; Seq ID No: 47 Ac-D-Bheg-Leu-Asp-He-N MeVal-Trp; Seq ID No: 20 Ac-D-Bheg-Leu-Asp-Chx-N Melle-Trp; Seq ID No: 49 Ac-D-Bheg-Leu-Asp-He-N MeChx-Trp; Seq ID No: 20 Ac-D-Bheg-Arg-Asp-lie-N MeChx-Trp; Seq ID No: 21 Ac-D-Bheg-Lys-Asp-lie-N MeChx-Trp; Seq ID No: 22 Ac-D-Bheg-Orn-Asp-Ile-N MeChx-Trp; Seq ID No: 38 Ac-D-Bheg-Asp-Asp-Ile-N MeChx-Trp; Seq ID No: 24 Ac-D-Bheg-Glu-Asp-He-N MeChx-Trp; 'Seq ID No: 25 Fmoc-D-Bheg-Leu-Phe-Ile-N-Melle-Trp; Seq ID No: 41 Fmoc-D-Bheg-Leu-Asn-He-N-Melle-Trp; Seq ID No: 55 Fmoc-D-Bheg-Leu-Glu-Ile-N-Melle-Trp; Seq ID No: 42 Fmoc-D-Bheg-Leu-Gln-He-N-Melle-Trp; Seq ID No: 43 Fmoc-D-Bheg-Leu-Tyr-Ile-N-Melle-Trp; Seq ID No: 44 Fmoc-D-Bheg-Leu-Asp-Val-N-Melle-Trp; Seq ID No: 47 -? fe Fmoc-D-Bheg-Leu-Asp-lie-N-MeVal-Trp; Seq ID No: 20 Fmoc-D-Bheg-Leu-Asp-Chx-N-Melle-Trp; Seq ID No: 49 Fmoc-D-Bheg-Arg-Asp-Chx N-Melle-Trp; Seq ID No: 50 Fmoc-D-Bheg-Lys-Asp-Chx-N-Melle-Trp; Seq ID No: 51 F oc-D-Bheg-Orn-Asp-Chx-N-Melle-Trp; Seq ID No: 52 Fmoc-D-Bheg-Asp-Asp-Chx-N-Melle-Trp; Seq ID No: 53 F oc-D-Bheg-Glu-Asp-Chx-N-Melle-Trp; Seq ID No: 54 F oc-D-Bheg-Leu-Asp- He-N-MeChx-Trp; Seq ID No: 20 Fmoc-D-Bheg-Arg-Asp-He-N-MeChx-Trp; Seq ID No: 21 Finoc-D-Bheg-Lys-Asp-He-N-MeChx-Trp; Seq ID No: 22 Finoc-D-Bheg-Orn-Asp-lie- -MeChx-Trp; Seq ID No: 3.1 Fmoc -D-Bheg-? S -As - lie-N-MeChx-Trp; Soq ID No: Z \ Fiii'jc-D-Bb ^ q-Glu-? Sp-He- -MeCh -Trp; Sc - q ID No: 5 F - j - D - Bbeg - Leu - D - Asp - IIe - Ile - Trp; Seq ID lio: 2 Fmoc-D-Bheg-Leu-D-Asp-He-N-MeIle-Trp; Seq ID NO: 20 Fmoc-D-Bhg-Leu-D-? Sp-He-He-Trp; scq ID NO: 2 Fmoc-D-Bhg-Leu-D-Asp-He-N-Melle-Trp; Seq ID O: 20 c-D-Txg-Leu-sp-He-N-Melle-Trp; seq ID no.- 20 Ac-D-Txg-Orn-Asp-He-N-Melle-Trp; Seq ID NO: 38 Ac-D-Txg-Lys-Asp-Ile-N-Melle-Trp; Scq ID NO: 22 Ac-D-Txg-Asp-Asp-He-N-Melle-Trp; Seq ID NO.- 24 Ac-D-Txg-Glu-Asp-He-N-Melle-Trp; Seq ID O: 25 Ac-D-Txg-Phe-Asp-He-N-Melle-Trp; Seq ID NO: 39 Ac-D-Txg-Arg-Asp-He-N-Melle-Trp; Seq ID or: 21 Ac-D-Txg-Asp-He-N-Melle-Trp; Seq ID O: 40 Fmoc-D-Txg-Leu-Asp- He-N-Melle-Trp; Scq ID NO: 20 Fmoc-D-Txg-Orn-? Sp-He-N-Melle-Trp; Seq ID NO: 38 Fmoc-D-Txg-Lys-Asp-He-N-Melle-Trp; Seq ID No: 22 Fmoc-D -Txg-Asp-? Sp-Ilc N-Melle-Trp; Seq ID lio.- 24 Fmoc-D-Txg-Glu-Asp-He-N-Melle-Trp; Seq ID NO: 25 Finoc -D-Txg- Phe-? Sp- He-N-Mellé-Trp; ? cq ID NO: 39 F? Uoc.-D ~ Txg-Arg-Asp-He-N-MeIle-Trp; Seq ID NO: 21 Fmoc-D-Txg-Asp-He-N-Melle-Trp; Seq ID NO: 56 Ac-D-Txg-Leu-Phe-He-N-Melle-Trp; Seq ID NO: 41 Ac-D-Txg-Leu-Asn-He-N-Melle-Trp; Seq ID NO: 55 c-D-Txg-Leu-Glu-He-N-Melle-Trp; Scq ID NO: 42 Ac-D-Txg-Leu-Gln-He-N-Melle-Trp; Seq ID NO: 43 Ac-D-Txg-Leu-Tyr-Ile-N-Melle-Trp; Seq ID NO: 44 Ac-D-Txg-Leu-l-Nal-He-N-Melle-Trp; seq ID uncle: 45 Ac-D-Txg-Leu-2-Nal-He-N-MeIle-Trp; Seq ID No: 45 c-D-Txg-Leu-Trp-He-N-Melle-Trp; Seq ID No: 46 c-D-Txg-Leu-Asp-Val-N-Melle-Trp; Seq ID NO: 47 c-D-Txg-Leu-sp-He-N-MeVal-Trp; Seq ID NO: 20 Ac-D-Txg-Leu-sp-Chx-N-Melle-Trp; Seq ID NO: 49 c-D-Txg-Leu-sp-He-N-MeChx-Trp; Scq ID lio: 20 ? c-D-Txg-? rg-? sp-Ilc-! t MeChx-Trp; Scq ID lio: 21 Ac-D-Txg-Lys-? Sp-He-N-MeClx-Trp; ID ID: 22 c-D-Txg-Orn-? sp-I.lo-N-MeChx-Trp; Scq ID NO: 38 ? c n-T.xq-? ^ p-? rp-lle-N-MeChx-Trp; r'r ID Vu: 24 ? c-D T > : g-G.lu-? sp-lle-N-MeCl? x-Trp; - TD lio. 25 Fít-ac-D-T; - q-Leu-Phe-Ile-N-Mele-Trp; r- ID no: 41 Fmoc -D-Txg-Leu-Asniere-N-Melle-Trp; Seq ID No: 55 Fmoc -D-Txg-Leu-Glu-Ile-N-Melle-Trp; Seq ID No: 42 Fmoc -D-Txg -Leu-Gln lie -N-Melle-Trp; Seq ID No: 43 * Fmoc -D-Txg- eu-Tyr-Ile-N-Melle-Trp; Seq ID No: 44 Fmoc -D-Txg- Leu- Asp- to -N-Melle-Trp; Seq ID No: 47 Fmoc-D-Txg-Leu-Asp-Ile-N-MeVal-Trp; Seq ID No: 20 Fmoc-D-Txg-Leu-Asp-Chx-N-Melle-Trp; Seq ID No: 49 Fmoc -D-Txg- Arg -Asp- Chx-N-Melle -Trp; Seq ID No: 50 Fmoc -D-Txg-Lys -Asp- Chx-N-Melle-Trp; Seq ID No: 51 Fmoc -D-Txg- Orn-Asp- Chx-N-Melle-Trp; Seq ID No: 52 Fmoc -D-Txg- Asp- Asp- Chx-N-Melle-Trp; Seq ID No: 53 Fmoc-D-Txg-Glu-Asp-Chx-N-Melle-Trp; Seq ID No: 54 Fmoc-D-Txg-Leu-Asp-He-N-MeChx-Trp; Seq ID No: 20 Fmoc-D-Txg-Arg-Asp-Ile-N-MeChx-Trp; Seq ID No: 21 Fmoc -D-Txg-Lys -Asp- H -N-MeChx-Trp; Seq ID No: 22 Fmoc -D-Txg-Orn- Asp-Ile-N-MeChx-Trp; Seq ID No: 38 Fmoc-D-Txg-Asp-Asp-Ile-N-MeChx-Trp; Seq ID No: 24 Fmoc-D-Txg-Glu-Asp-Ile-N-MeChx-Trp; Seq ID No: 25 Et-D-Bhg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Bz-D-Bhg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Pya-D-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 Cxi -D-Bhg-Leu-Asp-lie-N-Melle-Trp; Seq ID No: 20 Ada-D-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 Cxi (U) -D-Bhg-Leu-Asp-Ile-N-Melle-Trp; s See IIDD NOo :: 20 Me (U) -D-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 tBu-D-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 CF3C0-D-Bhg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 E-D-Bheg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Bz-D-Bheg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 Pya-D-Bheg-Leu-Asp-Ile-N-Melle-Trp; Seq ID No: 20 Cxl-D-Bheg-Leu-Asp-He-N-Melle-Trp; Seq ID No: 20 Ada -D-Bhe -Leu- Asp- He- N-Melle- Trp; Seq ID No: 20 Cxi (U) -D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID NO: 20 Me (U) -D-Bheg-Leu-Asp-He-N-Melle-Trp; seq ID O: 20 tBu-D-Bheg-Leu-Asp-He-N-Melle-Trp; Seq ID NO: 20 CF3C0-D-Bheg-Leu-Asp-He-N-Melle-Trp; Seq ID NO-. twenty Ac-D-Bheg-Leu-D-Asp-He-He-Trp; Seq ID NO:? Or Ac-D-Bheg-Leu-D-Asp- Ile-N-Melle-Trp; Seq ID No: 20 Ac -D-Bhg- Leu-D- Aspile-Ile-Trp; Seq ID No: 2 Ac -D-Bhg- eu-D- Asp- He-N-Melle-Trp; Seq ID No: 20 Ac -D-Bhg - Leu -Asp- Phe -N-Melle -Trp; Seq ID No: 56 Ac -D-Bhg- Orn-Asp- he -N-Melle-Trp; Seq ID No: 57 Ac -D-Bhg-Lys -Asp- he -N-Melle-Trp; Scq ID No: 58 Ac -D- Bhg -Asp- Asp- Phe -N-Melle-Trp; Seq ID No: 59 Ac -D-Bhg-Gl-Asp-Phe-N-Melle -Trp; Seq ID No: 60 Ac -D- Bhg- Phe-Asp- Phe-N-Melle-Trp; Seq ID No: 61 Ac -D-Bhg-Arg-Asp-Phe-N-Melle-Trp; Seq ID No: 62 Ac -D- Bheg-Leu -Asp- Phe -N-Melle- Trp; Seq ID No: 63 Ac-D-Bheg-Orn-Asp-Phe-N-elle-Trp; Seq ID No: 57 Ac-D-Bheg-Lys-Asp-Phe-I- -Melle-Trp; Seq ID No: 58 Ac-D-Bheg-Asp-Asp-Phe-N-Melle-Trp; Seq ID No: 59 Ac-D-Bheg-Glu-Asp-Phe-N-Melle-Trp; Seq ID or: 60 Ac-D-Bheg-Phe-Asp-Phe-N-Melle-Trp; Seq ID No: 61 Ac-D-Bheg-Arg-Asp-Phe-N-Melle-Trp; Seq ID No: 62 Ac-D-Bhg - Leu-N-MeAsp-He-Ile-Trp; and seq ID O: 15 Ac-D - Bhg-Arg -Asp- He-He-Tyr (CHO). seq ID No: 64 5 A method for inhibiting high levels of endothelin comprising the administration to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in dosage form per unit A pharmaceutical composition adapted for administration as an endothelin antagonist comprising an apolitically effective tei amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier / 7. A method for you. tie hypertension that comprises administration to a to claim 1 in dosage form per unit A pharmaceutical composition adapted for administration as an antihypertensive agent comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a "pharmaceutically acceptable excipient, diluent or carrier". V ^ * ^ r 9 A method for you to tie up metabolic and endocyte disorders comprising [administering to a guest suffering therefrom a therapeutically effective amount of a compound according to claim 1 in dosage form per unit A phamaceutical composition adapted for administration as an agent for treating metabolic and endocrine disorders that compiles an amount - ^^ Therapeutically effective of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, dilusoi or carrier 1 A method for treating congestive heart failure and myocardial infarction comprising 0 administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form of dose per unit. A Eu-chemical composition adapted for adininitiation as an agent for treating congestive heart failures and myocardial infarcts which encodes a therapeutically effective amount of a compound according to Claim 1 in connection with an excipient, diluent or carrier. pharmaceutically acceptable 13. A method for treating endotoxic attacks comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in phot dose per unit. 14. A pharmaceutical composition adapted for administration as a therapeutically effective amount agent of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 15. A method for you to bind subarachnoid hemorrhages comprising administering to a host suffering therefrom a therapeutically effective amount of a The compound according to claim 1 in the form of a dose per unit. 16. A pharmaceutical composition adapted for administration as an agent for treating subarachnoid hemorrhages comprising a therapeutically effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 17. A method for treating arrhythmias comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form of doses per unit. A pharmaceutical composition adapted for administration as an agent treating arrhythmias comprising a Therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 19. A method for treating asthma comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form of dose per unit. > > J * 20. A phannaceutical composition adapted for administration as an agent for treating asthma comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. A method for you to bind acute and clonic renal failures comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form of dose per unit 22. A pharmaceutical composition adapted for administration as an agent for treating acute and chronic renal failure comprising a therapeutically effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. t 23 A method for treating preclaims comprising administering to a user suffering therefrom a therapeutically effective amount of a compliant compound # to . Claim 1 in the form of dose per unit. A pharmaceutical composition adapted for administration as an agent for treating preclaims comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. lt ^ 25. A method for you to bind diabetes comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form of doses per unit. 26. A pharmaceutical composition adapted for administration as an agent for treating diabetes comprising a therapeutically effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 27 A method for treating neurological disorders, especially 0 vasospasms, brain attacks and head injuries, comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in 1? of dose per unit. 28. A pharmaceutical composition adapted for administration as a neurological agent, especially vasospasms and cerebral attacks and comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 29. A method for treating pulmonary hypertension which comprises administering to a host suffering therefrom a therapeutically effective amount of an ingredient according to claim 1 in dosage form per unit I 30 A pharmaceutical composition adapted for administration as an agent for treating pulmonary hypertension comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with an excipient, diluent or pharmaceutically acceptable carrier. 5 ^^ 3 1. A method for the expression of ischemic diseases comprising administering to a host a therapeutically effective amount of a compound according to claim 1 in the form of a dose per unit. 0 32 A pharmaceutical composition adapted for administration as an agent for treating ischemic diseases comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 33. A method of protection against damage to the gastric mucosa or to treat ischemic bowel comprising administering to a host a therapeutically effective amount of a compound according to claim 1 in the form of doses per unit. for administration as an agent for protecting against damage to the gastric mucosa or for treating ischemic diseases in the intestines comprising a therapeutically effective amount of a compound according to Claim I in admixture with a pharmaceutically acceptable excipient, diluent or carrier. . A method for treating atherosclerotic disorders including Raynaud's disease which comprises administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form 15 dose per unit. # 36 A phannaceutical composition adapted for administration as an agent for treating atherosclerotic disorders including Raynaud's disease comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. . 37 A method for you to bind the restenosis comprising administering to a user suffering therefrom a therapeutically effective amount of a compliant compound # to claim 1 in dosage form per unit. 38. A pharmaceutical composition adapted for administration as an agent for treating restenosis comprising a therapeutically effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 0 ^ 39. A method for treating angina comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form of doses per unit. 40. A pharmaceutical composition adapted for administration as an agent for treating angina comprising a therapeutically effective amount of a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. A method for treating cancer comprising administering to a host who suffers therefrom a therapeutically effective amount of a compound according to claim 1 in the form of doses per unit A phamaceutical composition adapted for administration as an agent for treating cancer comprising a therapeutically effective amount of a compound according to Claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or acceptor. A method for treating bleeding attacks comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 1 in the form of dose per unit 44 A pharmaceutical composition adapted for administration as an agent 0"* a compound according to claim 1 in admixture with a pharmaceutically acceptable excipient, diluent or carrier One method is to a compound of Formula 1 AA'-AA2-AA'-AA4-AA5-AA6 I 5 wherein AA1 is Seq ID Number 1 wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, # arylalkyl heteroaryl. Iluorenylmethyl. -N-R2, J where R and R2 are each the same or different and each one is # hydrogen, ?? alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, fluorenylmethyl, O II, -C-OR, where R is as defined above, 0 -OR2, where R2 is as defined above, OR -NCNR ', where R and R are as R2 R2 above, OR ii - CC (R9) 3, where R9 is -F, Cl, Bi or I, CH2-OR, where R is as defined above, O-NCR, where R2? is hydrogen or alkyl I,.
5. 5 RA and R ~ is as defined above, OR -NC 11-OR ',, where R and R' are as defined I R2A above excluding R 'is hydrogen or O # \ (f -C-R2, wherein R2 is as defined above, R1 is hydrogen or alkyl, Z is -O-, -S (O) m, where m is zero or an integer or 1 or 2.15 where R2 is as defined above - (CI-.) ,, -, where n is zero or an integer of 1, 2, 3 or 4, - (CH2) "- CH = CH- (CH >) M -, cn where 11 and n ' are each independently identical or different and each as defined above for n, 20 OR II -c-, -, where R and l <~ are as defined above or iV i -C-, where R2 and R: are each * same or different ^? I,. -R1 and each one is as defined above, X and Y are equal and substituted in the same position on the aromatic chain and each 5 can be 1, 2 , 3 or 4 substitutes chosen from the group consisting of hydrogen, halogen, alkyl,? * ¡-CO2R2, where R2 is as defined above, -CO NR, where R and IV are as defined R 'above, -NR2, where R2 and R "are as defined R I-, above or nitro or where R, Z, X and Y are as defined by araba, AA "is wherein R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, anl, heteroaryl. -N-R3B, wherein R2b and IV1 'are each the same or R2h or different and each is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, -OR2b, wherein R2b is as described above OR -CN-R31 ', where R21' and R'1 'are each equal and each is ^ "as defined above for IV" and RJD, O II -C-R21 ', where R21' is as defined ai i went NH -NI lC- El-R21 ', where lV' is as defined above or O II C-OR 2Zb0, where R, 2zb "is as defined above and R1 and n are as defined above or AA2 is absent; AA is O IV l ^ * * eenn ddoonnddee WW eess --CC II-- or -C-, IV R5 is hydrogen, alkyl, 5 aryl, eroai il, II -CN-1V '\ where R21' and R'1 ' are each R b 'the same or different' s and each is as defined above, 0 OR II -C-R21 ', where R21' is as defined above or O -C-OR ', where IV is as defined above and R1 and n are as sc d ine up or AA 'is absent. Absent or each one independently wherein R 'is hydrogen, alkyl, alkenyl, l? alkynyl, aryl or heter? aryl and R and n are as defined above, 15 AA ° es 0 wherein R7 is aryl or heteroaryl i is O C'-OR, where R is as defined above. -OR1, where R1 is as defined above, N-R1, wherein R1 is as defined above R or 5 -CH2-OR. ', Wherein R1 is as defined above and R1 and n are as defined above; The stereochemistry in C in AA1-AA2-AA3-AA4o-AA 'is ü, L or DL and the stereochemistry in C in AAf' is L, or a pharmaceutically acceptable salt of the same as «• comprises the coupling in sequential steps of the amino acids chosen from AA1, AA2, AA \ AA4, AA5 or AA6 with the preceding amino acid using the conventional peptide synthesis methodology and then the conventional deprotection to produce a compound of Formula I and, if desired, convert a compound of Formula 1 to a salt Pharmaceutically acceptable salt of a compound of Formula I by conventional methodology and, if desired, converting the pharmaceutically acceptable salt of a compound of Formula 1 to a compound of Formula I by conventional l-1-methodology